Macrocycles as factor xia inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.13/577,666, filed on Aug. 8, 2012, which is a U.S. national phase ofInternational Application No. PCT/US2011/024308, filed on Feb. 10, 2011,which claims priority of U.S. Ser. No. 61/303,423, filed Feb. 11, 2010,and U.S. Ser. No. 61/405,338, filed Oct. 21, 2010, incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are inhibitors of factor XIa and/orplasma kallikrein, compositions containing them, and methods of usingthem, for example, for the treatment or prophylaxis of thromboembolicdisorders.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thusdiscovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to factor VII(FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates factor IX (FIX) and factor X (FX) that leads to the productionof factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for antithrombotic therapy.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectiveinhibitors of serine protease enzymes, especially factor XIa and/orplasma kallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two, other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

ring A is independently a C₃₋₁₀ carbocycle or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

ring B is independently a benzene ring or a 5- to 6-membered heteroarylcomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

ring C is independently a benzene ring or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

L₁ is independently selected from the group consisting of: a bond,—CHR⁵—, —CHR⁵CHR⁵—, —CR⁵═CR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—;

L is independently selected from the group consisting of:

—C₁₋₆ alkylene-(C₃₋₈ carbocycle)-C₀₋₄ alkylene-, and —C₁₋₆ alkylene-(5-to 6-membered heterocycle)-C₀₋₄ alkylene-; wherein said heterocyclecomprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p); wherein said alkylene is substituted with 0-2R⁷ and optionally one or more of the carbon atoms of said alkylene maybe replaced by O, S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO, OCONH, NHCO₂,SO₂NH, NHSO₂, CON(C₁₋₄ alkyl), or N(C₁₋₄ alkyl)CO; wherein saidcarbocycle and heterocycle are substituted with 0-2 R^(7a);

Y is independently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄alkyl)-, —NHCONH—, —SO₂NH—, —NHCO₂—, and —NHSO₂—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,C₁₋₄haloalkyl, OCH₂F, OCHF₂, OCF₃, CN, NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, and phenyl substitutedwith 0-2 R^(a);

R² is independently a 5- to 7-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃,CN, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and—SO₂N(C₁₋₄ alkyl)₂;

R³ is independently selected from the group consisting of: H, halogen,OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —CH₂CO₂H,and C₃₋₆ cycloalkyl;

R⁴ is independently selected from the group consisting of: H, and C₁₋₄alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,NH(C₁₋₄alkyl), —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —C(O)NH(CH₂)₂O(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and

R⁷ and R^(7a) are, independently at each occurrence, selected from thegroup consisting of: halogen, OH, NH₂, CH₂NH₂, CH₂F, CHF₂, CF₃, OCH₂F,OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH,CH₂O(C₁₋₄ alkyl), CH₂—O—(CH₂)₁₋₄O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl),CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂,—OCO(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,—(CO)₀₋₁(CH₂)₀₋₁—C₃₋₆ carbocycle, and —(CO)₀₋₁(CH₂)₀₋₁-(4- to 6-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein said carbocycle andheterocycle are substituted with 0-2 R⁸;

R⁸ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, CH₂OH, CO₂H,CO₂(C₁₋₄ alkyl), CONH₂, and C₁₋₄ alkyl;

R⁹ is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), O,and S(O)_(p);

R^(a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl;

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In a second aspect, the present invention provides compounds of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, within the scope of the first aspect,wherein:

ring A is independently a 6-membered carbocycle, a 9- to 10-memberedcarbocycle, or a 5- to 10-membered heterocycle comprising: carbon atomsand 1-3 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p);

ring B is independently selected from the group consisting of:imidazole, oxazole, oxadiazole, triazole, pyridine, pyridazine,pyrimidine, and benzene; and

ring C is independently selected from the group consisting of: benzene,pyridine, indazole, indole, benzimidazole, quinoline, isoquinoline andquinazoline.

In a third aspect, the present invention provides compounds of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, within the scope of the first or secondaspect, wherein:

ring A is independently selected from the group consisting of: benzene,cyclohexane, indane, tetrahydronaphthalene, naphthalene,dihydroisoxazole, isoxazole, pyrazole, imidazole, triazole, piperidine,indazole, indole, benzimidazole, quinoline, isoquinoline,tetrahydroquinoline, and tetrahydroisoquinoline;

is independently selected from the group consisting of:

and

is independently selected from the group consisting of:

In a fourth aspect, the present invention provides compounds of Formula(II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

is independently selected from the group consisting of:

L₁ is independently selected from the group consisting of: a bond,—CHR⁵CHR⁵—, —CR⁵═CHR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—;

L is independently selected from the group consisting of:

—C₁₋₆ alkylene-(C₃₋₈ carbocycle)-C₀₋₄ alkylene-, and —C₁₋₆ alkylene-(5-to 6-membered heterocycle)-C₀₋₄ alkylene-; wherein said heterocyclecomprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p); wherein said alkylene is substituted with 0-2R⁷ and optionally one or more of the carbon atoms of said alkylene maybe replaced by O, S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO, OCONH, SO₂NH, orCON(C₁₋₄ alkyl); wherein said carbocycle and heterocycle are substitutedwith 0-2 R^(7a);

Y is independently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄alkyl)-, —NHCONH—, and —SO₂NH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CN, NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H, —CH₂NH₂, —CONH₂,—CONH(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is independently a 5- to 6-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NH, O, and S(O)_(p), whereinsaid heterocycle is substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃,CN, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl),and —CON(C₁₋₄ alkyl)₂;

R³ is independently selected from the group consisting of: H, halogen,OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and—CH₂CO₂H;

R⁴ is independently selected from the group consisting of: H and C₁₋₄alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,NH(C₁₋₄alkyl), —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—C(O)NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂,—CH₂CONH₂, and

R⁷ and R^(7a) are, independently at each occurrence, selected from thegroup consisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, CH₂OH,CH₂O(C₁₋₄ alkyl), CO₂H,

CO₂(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, —OCO(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄alkyl)₂, C₁₋₄ alkyl, and —(CO)₀₋₁-(4- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p); wherein said heterocycle is substituted with0-2 R⁸;

R⁸ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CHF₂, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In a fifth aspect, the present invention provides compounds of Formula(IIa) or Formula (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In a sixth aspect, the present invention provides compounds of Formula(IIc) or Formula (IId):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In a seventh aspect, the present invention provides compounds of Formula(IIe) or Formula (IIf):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the fourth aspect.

In an eighth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) a stereoisomer, atautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any of the above aspects, wherein:

L₁ is independently selected from the group consisting of: a bond,—CH₂CH₂—, —CH═CH—, —C(Me)=CH—, —C≡C—, and —CH₂NH—;

L is independently selected from the group consisting of:

—(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—, —CH₂O(CH₂)₁₋₄-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(phenylene)-CONH(CH₂)₀₋₂—, —(CH₂)₁₋₂-phenylene-CON(C₁₋₄alkyl)(CH₂)₀₋₂—, —(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—,—CH₂-pyrimidinylene-(CH₂)₀₋₃—,

wherein each ring moiety is substituted with 0-2 R^(7a);

Y is independently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

R¹ is, independently at each occurrence, selected from: halogen, CN, OH,CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄alkyl), NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄ alkyl)₂, —C(═NH)NH₂, —C(O)NH₂,—CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —SO₂NH₂;

R³ is independently selected from the group consisting of: H, halogen,OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and—CH₂CO₂H; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, and

In a ninth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any of the above aspects, wherein:

L₁ is independently selected from the group consisting of: a bond,—CH₂CH₂— and —CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, CN, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CH₂F, CHF₂,CF₃, OCH₂F, OCHF₂, OCF₃, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —C(═NH)NH₂;

R³ is independently selected from the group consisting of: H, halogen,CN, CF₃, CO₂H, CO₂(C₁₋₄ alkyl), and C₁₋₄ alkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl),—NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂, —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄alkyl), and

In a tenth aspect, the present invention includes compounds of Formula(I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrugthereof, within the scope of any one of the above aspects, wherein:

L is independently selected from the group consisting of:

—CH₂-phenylene-(CH₂)₀₋₃—, —CH₂O(CH₂)₂₋₄-phenylene-(CH₂)₀₋₁—,—CH₂-phenylene-CONH(CH₂)₀₋₂—, —CH₂-phenylene-CON(C₁₋₄ alkyl)(CH₂)₀₋₂—,—CH₂-pyridinylene-(CH₂)₀₋₃—, —CH₂-pyrimidinylene-(CH₂)₀₋₃—,

wherein each ring moiety is substituted with 0-1 R^(7a);

Y is independently selected from the group consisting of: CH₂, O, NH,N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

L₁ is independently selected from the group consisting of: a bond and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl),and —C(═NH)NH₂;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, and CN;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl),—NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In an 11th aspect, the present invention includes compounds of Formula(III) or Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R^(7a);

Y is independently selected from the group consisting of: CH₂, O, NH,N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

L₁ is independently selected from the group consisting of: a bond and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl),and —C(═NH)NH₂;

R^(1b) is independently selected from the group consisting of: H andhalogen;

R² is independently a 5-membered heterocycle selected from: triazolyland tetrazolyl;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, and CN;

R^(6a) is independently selected from the group consisting of: H,halogen, NH₂, CO₂H, CONH₂, CO₂(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H,—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In a 12th aspect, the present invention includes compounds of Formula(IIIb) or Formula (IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R^(7a);

Y is independently selected from the group consisting of: CH₂, O, NH,—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

L₁ is independently selected from the group consisting of: a bond and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, OCHF₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —C(═NH)NH₂;

R^(1b) is independently selected from the group consisting of: H andhalogen;

R³ is independently selected from the group consisting of: H, halogen,C₁₋₄ alkyl, and CN;

R^(6a) is independently selected from the group consisting of: H,halogen, NH₂, CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂O(C₁₋₄ alkyl),

—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In a 13th aspect, the present invention includes compounds of Formula(IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L-Y is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R^(7a);

L₁ is independently selected from the group consisting of: a bond and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CHF₂, and OCHF₂;

R^(1b) is independently selected from the group consisting of: H andhalogen;

R² is independently a 5-membered heterocycle selected from: pyrazolyl,imidazolyl, triazolyl, and tetrazolyl;

R³ is independently selected from the group consisting of: H andhalogen;

R^(6a) is independently selected from the group consisting of: H,halogen, NH(C₁₋₄ alkyl), and NHCO₂(C₁₋₄ alkyl); and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, N(C₁₋₄ alkyl)₂.

In a 14th aspect, the present invention includes compounds of Formula(IIIc) or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, within the scope of the 13thaspect, wherein:

L-Y is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R^(7a);

R² is independently triazolyl or tetrazolyl; and

R^(6a) is independently selected from the group consisting of: H,halogen, and NHCO₂(C₁₋₄ alkyl).

In a 15th aspect, the present invention includes compounds of Formula(IIIc) or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, within the scope of the 13thaspect or 14th aspect, wherein:

L-Y is independently selected from the group consisting of:

R¹ is independently selected from the group consisting of: F, Cl, Me,OMe, COMe, CN, CHF₂, and OCHF₂;

R^(1b) is independently selected from the group consisting of: H and F;

R² is tetrazolyl;

R³ is independently selected from the group consisting of: H and Cl; and

R^(6a) is independently selected from the group consisting of: H, F, andNHCO₂Me.

In a 16th aspect, the present invention includes compounds of Formula(V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, within the scope of the first, second orthird aspect, wherein:

ring B is independently selected from the group consisting of: imidazoleand pyridine; and

R¹ is independently selected from the group consisting of: C₁₋₄ alkyland CH₂NH₂.

In another aspect, the present invention includes compounds of Formula(V): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring B is independently selected from the group consisting of:

L is independently —CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is independently selected from the group consisting of: —CH₂—, —CONH—,and NH;

R³ is independently selected from the group consisting of: H, F, Cl, andMe; and

R^(6a) is independently selected from the group consisting of: H and—NHCO₂Me.

In a 17th aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the 24th aspect.

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of the fourth aspect, wherein:

is independently selected from the group consisting of:

In another aspect wherein:

is independently selected from the group consisting of:

In another aspect, wherein:

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of the fourth aspect, wherein:

is independently selected from the group consisting of:

In another aspect wherein:

is independently selected from the group consisting of:

In anotheraspect wherein:

is independently selected from the group consisting of:

In another aspect wherein:

In another aspect wherein:

In another aspect, the present invention includes compounds of Formula(I), (II), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of any of the above aspects, wherein:

R² is independently a 5-membered heterocycle substituted with 0-1R^(2a), wherein said heterocycle is selected from: pyrazolyl,imidazolyl, triazolyl, and tetrazolyl; and

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, NH₂, CH₂OH, CO₂H, C₁₋₄ alkyl, —CONH₂,—CONH(C₁₋₄ alkyl), and —CON(C₁₋₄ alkyl)₂.

In another aspect, the present invention includes compounds of Formula(I), (II), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,within the scope of any of the above aspects, wherein:

R² is independently selected from the group consisting of: triazolyl andtetrazolyl.

In another embodiment, ring A is independently selected from the groupconsisting of: phenyl, cyclohexyl, and 5,6,7,8-tetrahydroisoquinolinyl.

In another embodiment, ring A is phenyl.

In another embodiment, ring A is cyclohexyl.

In another embodiment, ring A is tetrahydroisoquinoline.

In another aspect, ring A is

wherein R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CH₂F, CHF₂, OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl),and —C(═NH)NH₂.

In another aspect, ring A is

is independently selected from the group consisting of:

In another embodiment, ring B is independently selected from the groupconsisting of: imidazole, oxadiazole, pyridine, pyridazine, and benzene.

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

In another embodiment,

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

is independently selected from the group consisting of:

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂—, —CH═CH—, —C(Me)=CH—, —C≡C—, and—CH₂NH—.

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂—, —CH═CH—, and —C(Me)=CH.

In another embodiment, L₁ is independently selected from the groupconsisting of: a bond, —CH₂CH₂— and —CH═CH—.

In another embodiment, L₁ is a bond.

In another embodiment, L₁ is —CH═CH—.

In another embodiment, L is independently selected from the groupconsisting of: —(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—,—CH₂O(CH₂)₁₋₄-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(phenylene)-CONH(CH₂)₀₋₂—,

—(CH₂)₁₋₂-phenylene-CON(C₁₋₄ alkyl)(CH₂)₀₋₂—,—(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—, —CH₂-pyrimidinylene-(CH₂)₀₋₃—,

wherein each ring moiety is substituted with 0-2 R^(7a).

In another embodiment, L is independently selected from the groupconsisting of: —(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—, —CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(phenylene)-CONHCH₂—, and

wherein said phenylene and pyridinylene are optionally substituted with1-2 R⁷; optionally one or more of the carbon atoms of said alkylene andalkenylene may be replaced by O, S, NH, N(C₁₋₄ alkyl), CONH—, orCON(C₁₋₄ alkyl).

In another embodiment, L is independently selected from the groupconsisting of: —(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—, —CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—,

—(CH₂)₁₋₂-(phenylene)-CONHCH₂—, and

wherein said phenylene and pyridinylene are optionally substituted with1-2 R⁷; optionally one or two of the carbon atoms of said alkylene andalkenylene may be replaced by O, NH, N(C₁₋₄ alkyl), CONH, or CON(C₁₋₄alkyl).

In another embodiment, L is independently selected from the groupconsisting of: —(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—, —CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(phenylene)-CONHCH₂—, and

wherein said phenylene and pyridinylene are optionally substituted with1-2 R⁷.

In another embodiment, L is independently selected from the groupconsisting of: —(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—,—CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—, and —(CH₂)₁₋₂-(phenylene)-CONHCH₂—;wherein said phenylene is optionally substituted with 1-2 R⁷.

In another embodiment, L is —(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—; whereinsaid pyridinylene is optionally substituted with 1-2 R⁷.

In another embodiment, Y is independently selected from the groupconsisting of: —CH₂—, O, NH, N(C₁₋₄ alkyl), —NHCO—, —CONH—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—.

In another embodiment, Y is independently selected from the groupconsisting of: —CH₂—, O, NH, NMe, —CONH—, —NHCO—, —CONHCH₂—, —CONMeCH₂—,—OCONH—, —NHCONH—, and —SO₂NH—.

In another embodiment, Y is —CONH—.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CN, NH₂, NH(C₁₋₄alkyl)², N(C₁₋₄ alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H,—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl),

—CH₂NHCO₂(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, OH, CHF₂, CF₃, OCF₃, CN, NH₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄alkyl), —OCH₂CO₂H, —CH₂NH₂, —CONH₂,

—CONH(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom: halogen, CN, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl)₂, N(C₁₋₄ alkyl)₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —SO₂NH₂.

In another embodiment, R¹ is, independently at each occurrence, selectedfrom: halogen, CN, OH, OCF₃, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄alkyl), NH₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, and —SO₂NH₂.

In another embodiment, R¹ is selected from the group consisting of:halogen, C₁₋₄ alkyl, CHF₂, and CO(C₁₋₄ alkyl).

In another embodiment, R² is a 5-membered heterocycle substituted with0-1 R^(2a), wherein said heterocycle is independently selected from:pyrazolyl, imidazolyl, triazolyl, and tetrazolyl.

In another embodiment, R² is independently selected from the groupconsisting of: triazolyl and tetrazolyl.

In another embodiment, R² is tetrazolyl.

In another embodiment, R³ is independently selected from the groupconsisting of: H, C₁₋₄ alkyl, and halogen.

In another embodiment, R³ is independently selected from the groupconsisting of: H and halogen.

In another embodiment, R³ is independently selected from the groupconsisting of: H and Cl.

In another embodiment, R³ is H.

In another embodiment, R³ is Cl.

In another embodiment, R⁴ is H.

In another embodiment, R⁵ is, independently at each occurrence, selectedfrom the group consisting of: H and C₁₋₄ alkyl.

In another embodiment, R⁵ is, independently at each occurrence, selectedfrom the group consisting of: H and methyl.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —C(O)NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl),—(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), and —CONH₂.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂,—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H,—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, NH₂, CO₂H, CO₂(C₁₋₄ alkyl),CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄ alkyl),—CH₂NHCO₂(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), and —CONH₂.

In another embodiment, R⁶ is, independently at each occurrence, selectedfrom the group consisting of: halogen, CO₂H, CO₂(C₁₋₄ alkyl), NH₂,NHCO₂(C₁₋₄ alkyl), and —CH₂NHCO₂(C₁₋₄ alkyl).

In another embodiment, R⁶ is, independently at each occurrence, isselected from the group consisting of: halogen, NH₂, NHCO₂(C₁₋₄ alkyl),and —CH₂NHCO₂(C₁₋₄ alkyl).

In another embodiment, R⁶ is, independently at each occurrence, isselected from the group consisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, NH₂, CO₂H, CONH₂, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄alkyl), and

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, NH(C₁₋₄ alkyl), and NHCO₂(C₁₋₄ alkyl).

In another embodiment, R^(6a) is independently selected from the groupconsisting of: H, halogen, and NHCO₂(C₁₋₄ alkyl).

In another embodiment, R^(6a) is R^(6a) is independently selected fromthe group consisting of: H, F, and NHCO₂Me.

In another embodiment, R⁷ is independently selected from the groupconsisting of: halogen, C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In another embodiment, R⁷ is independently selected from the groupconsisting of: halogen, and C₁₋₄ alkyl.

In another embodiment, R^(7a) is independently selected from the groupconsisting of: halogen, C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.

In another embodiment, R^(7a) is independently selected from the groupconsisting of: halogen, and C₁₋₄ alkyl.

In another aspect, the present invention provides, inter alia, acompound of Formula (I-1):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

ring A is a C₃₋₁₀ carbocycle or a 5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

ring B is a benzene ring or a 5- to 6-membered heteroaryl comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

ring C is a benzene ring or a 5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);

L₁ is selected from the group consisting of: a bond, —CHR⁵CHR⁵—,—CR⁵═CR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—,and —CR⁵R⁵—;

L is selected from the group consisting of:

—C₁₋₆ alkylene-(C₃₋₈ carbocycle)-C₀₋₄ alkylene-, and —C₁₋₆ alkylene-(5-to 6-membered heterocycle)-C₀₋₄ alkylene-; wherein said heterocyclecomprises: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); wherein said carbocycle and heterocycle are optionallysubstituted with 1-2 R⁷; optionally one or more of the carbon atoms ofsaid alkylene and alkenylene may be replaced by O, S, NH, N(C₁₋₄ alkyl),CO, CONH, NHCO, OCONH, SO₂NH, or CON(C₁₋₄ alkyl);Y is selected from the group consisting of: O, S, NH, N(C₁₋₄ alkyl),CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄ alkyl)₂, —CONH—, —NHCO—, —CONHCH₂—,—CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄ alkyl)-, —NHCONH—, —SO₂NH—,—NHCO₂—, and —NHSO₂—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,CHF₂, CF₃, OCF₃, CN, NH₂, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂,—CONH₂, —CONH(C₁₋₄ alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃, CN, NH₂,CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl),—CON(C₁₋₄ alkyl)₂, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and—SO₂N(C₁₋₄ alkyl)₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H;

R⁴ is selected from the group consisting of: H and C₁₋₄ alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,and —CH₂CONH₂;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, NH₂, —CH₂NH₂, CHF₂, CF₃, —NH(C₁₋₄ alkyl),—N((C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₁₋₄ alkyl; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(I-1), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

ring A is a 6-membered carbocycle or 5,6,7,8-tetrahydroisoquinoline;

ring B is selected from the group consisting of: imidazole, oxadiazole,pyridine, pyridazine, pyrimidine, and benzene; and

ring C is selected from the group consisting of: benzene and pyridine.

In another aspect, the present invention provides compounds of Formula(Ia), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring A is selected from the group consisting of: benzene, cyclohexane,and 5,6,7,8-tetrahydroisoquinoline;

is selected from the group consisting of:

and

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(II-1):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

L₁ is selected from the group consisting of: a bond, —CHR⁵CHR⁵—,—CR⁵═CHR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—,and —CR⁵R⁵—;

L is selected from the group consisting of:—(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—, —(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—,—CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—, —(CH₂)₁₋₂-(phenylene)-CONHCH₂—, and

wherein said phenylene and pyridinylene are optionally substituted with1-2 R⁷; optionally one or two of the carbon atoms of said alkylene andalkenylene may be replaced by O, S, NH, N(C₁₋₄ alkyl), CONH—, orCON(C₁₋₄ alkyl);

Y is selected from the group consisting of: CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄ alkyl)-, —NHCONH—, and —SO₂NH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH,CHF₂, CF₃, OCF₃, CN, NH₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl), —OCH₂CO₂H,—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —SO₂NH₂, and —C(═NH)NH₂;

R² is a 5- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(2a);

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, CN, NH₂, CO₂H,CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl), and —CON(C₁₋₄alkyl)₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H;

R⁴ is selected from the group consisting of: H and C₁₋₄ alkyl;

R⁵ is, independently at each occurrence, selected from the groupconsisting of: H, halogen, OH, and C₁₋₄ alkyl;

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —CONH₂,—C(O)NH(CH₂)₂O(C₁₋₄ alkyl), and —CH₂CONH₂;

R⁷ is, independently at each occurrence, selected from the groupconsisting of: halogen, OH, CF₃, C₁₋₄ alkoxy and C₁₋₄ alkyl; and

p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(I), (II), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

is selected from the group consisting of:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention provides compounds of Formula(I-1), (II-1), (IIa), (IIc), or (IIe), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

R² is a 5-membered heterocycle substituted with 0-1 R^(2a), wherein saidheterocycle is selected from: pyrazolyl, imidazolyl, triazolyl, andtetrazolyl; and

R^(2a) is, independently at each occurrence, selected from the groupconsisting of: OH, NH₂, CH₂OH, CO₂H, C₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄alkyl), and —CON(C₁₋₄ alkyl)₂

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), or (IIb), a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate, or a prodrug thereof,wherein:

R² is selected from the group consisting of: triazolyl and tetrazolyl.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂—, —CH═CH—,—C(Me)=CH—, —C≡C—, and —CH₂NH—;

L is selected from the group consisting of:—(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—, —(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—,—CH₂O(CH₂)₁₋₃-(phenylene)-(CH₂)₀₋₃—, —(CH₂)₁₋₂-(phenylene)-CONHCH₂—, and

wherein said phenylene and pyridinylene are optionally substituted with1-2 R⁷; optionally one or two of the carbon atoms of said alkylene andalkenylene may be replaced by O, NH, N(C₁₋₄ alkyl), CONH, or CON(C₁₋₄alkyl);

Y is selected from the group consisting of: CH₂, CH(C₁₋₄ alkyl), C(C₁₋₄alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is, independently at each occurrence, selected from: halogen, CN, OH,OCF₃, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), NH₂,—C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, and —SO₂NH₂;

R³ is selected from the group consisting of: H, halogen, OH, NH₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂,—CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂,—NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), and—CONH₂.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂— and—CH═CH—;

R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, CN, C₁₋₄ alkyl, CHF₂, CF₃, CO(C₁₋₄ alkyl), NH₂,—CH₂NH₂, and —C(═NH)NH₂;

R³ is selected from the group consisting of: H, halogen, CF₃, CO₂H,CO₂(C₁₋₄ alkyl), and C₁₋₄ alkyl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl),—CH₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl),—NHCO₂(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl), and —CONH₂.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L₁ is selected from the group consisting of: a bond, —CH₂CH₂— and—CH═CH—;

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,4-phenylene-, —CH₂-1,3-(4-halo-phenylene)-,—CH₂-1,4-(3-halo-phenylene)-, —CH₂-1,4-phenylene-(CH₂)₂—,—CH₂-1,3-(4-halo-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂O(CH₂)₃-1,3-phenylene-,—CH₂-1,3-phenylene-CONHCH₂—, —CH₂-2,6-pyridinylene-(CH₂)₂—,—CH₂-2,6-(3-halo-pyridinylene)-(CH₂)₂—, and

Y is selected from the group consisting of: —CH₂—, O, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

R³ is selected from the group consisting of: H, C₁₋₄ alkyl, and halogen;and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: halogen, CO₂H, CO₂(C₁₋₄ alkyl), NH₂, NHCO₂(C₁₋₄ alkyl),and —CH₂NHCO₂(C₁₋₄ alkyl).

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,4-phenylene-, —CH₂-1,3-(4-halo-phenylene)-,—CH₂-1,4-phenylene-(CH₂)₂—, —CH₂-1,3-(4-halo-phenylene)-(CH₂)₂—,—CH₂-1,3-phenylene-(CH₂)₃—, —CH₂-1,4-phenylene-(CH₂)₃—,—CH₂O(CH₂)₃-1,3-phenylene-, —CH₂-1,3-phenylene-CONHCH₂—,—CH₂-2,6-pyridinylene-(CH₂)₂—, —CH₂-2,6-(3-halo-pyridinylene)-(CH₂)₂—,and

Y is selected from the group consisting of: CH₂, O, NH, N(C₁₋₄ alkyl),—NHCO—, —CONH—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—;

R¹ is selected from the group consisting of: halogen, C₁₋₄ alkyl, CHF₂,CN, and CO(C₁₋₄ alkyl);

R³ is selected from the group consisting of: H, C₁₋₄ alkyl, and halogen;and

R⁶ is, independently at each occurrence, is selected from the groupconsisting of: halogen, NH₂, NHCO₂(C₁₋₄ alkyl), and —CH₂NHCO₂(C₁₋₄alkyl).

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,4-phenylene-, —CH₂-1,3-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-, —CH₂-1,4-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂O(CH₂)₃-1,3-phenylene-,—CH₂-1,3-phenylene-CONHCH₂—, —CH₂-2,6-pyridinylene-(CH₂)₂—,—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—, and

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is selected from the group consisting of: H, F, Cl, Me, COMe, andCHF₂;

R³ is selected from the group consisting of: H, Me, and Cl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, within the scope of any one of the above aspects,wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,3-phenylene-(CH₂)₂—, —CH₂-1,3-(4-F-phenylene)-,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂-2,6-pyridinylene-(CH₂)₂—, and—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(IIe) or (IIf) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a solvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,4-phenylene-, —CH₂-1,3-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-, —CH₂-1,4-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂O(CH₂)₃-1,3-phenylene-,—CH₂-1,3-phenylene-CONHCH₂—, —CH₂-2,6-pyridinylene-(CH₂)₂—,—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—, and

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R¹ is selected from the group consisting of: H, F, Cl, Me, COMe, andCHF₂;

R³ is selected from the group consisting of: H, Me, and Cl; and

R⁶ is, independently at each occurrence, selected from the groupconsisting of: F, NH₂, NHCO₂Me, and —CH₂NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(I-1), (II-1), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate,or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,3-phenylene-(CH₂)₂—, —CH₂-1,3-(4-F-phenylene)-,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂-2,6-pyridinylene-(CH₂)₂—, and—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(IIe) or (IIf) or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a solvate, or a prodrug thereof, wherein:

is selected from the group consisting of:

In another aspect, the present invention includes compounds of Formula(III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,4-phenylene-, —CH₂-1,3-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-, —CH₂-1,4-phenylene-(CH₂)₂—,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂O(CH₂)₃-1,3-phenylene-,—CH₂-1,3-phenylene-CONHCH₂—, —CH₂-2,6-pyridinylene-(CH₂)₂—,—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—, and

Y is selected from the group consisting of: CH₂, O, NH, NMe, —CONH—,—NHCO—, —CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R^(1b) is selected from the group consisting of: H and F;

R³ is selected from the group consisting of: H, Me, and Cl; and

R^(6a) is selected from the group consisting of: H, F, NH₂, and NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,3-phenylene-(CH₂)₂—, —CH₂-1,3-(4-F-phenylene)-,—CH₂-1,3-(4-F-phenylene)-(CH₂)₂—, —CH₂-1,3-phenylene-(CH₂)₃—,—CH₂-1,4-phenylene-(CH₂)₃—, —CH₂-2,6-pyridinylene-(CH₂)₂—, and—CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—CONHCH₂—, —CONMeCH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;

R^(1b) is selected from the group consisting of: H and F;

R³ is selected from the group consisting of: H and Cl; and

R^(6a) is selected from the group consisting of: H, F, NH₂, and NHCO₂Me.

In another aspect, the present invention includes compounds of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, a solvate, or a prodrug thereof, wherein:

L is selected from the group consisting of: —CH₂-1,3-phenylene-,—CH₂-1,3-phenylene-(CH₂)₂—, —CH₂-1,3-(4-F-phenylene)-(CH₂)₂—,—CH₂-1,3-phenylene-(CH₂)₃—, —CH₂-1,4-phenylene-(CH₂)₃—,—CH₂-2,6-pyridinylene-(CH₂)₂—, and —CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is selected from the group consisting of: CH₂, O, NH, —CONH—, —NHCO—,—OCONH—, —NHCONH—, —CONHCH₂—, and —SO₂NH—; and

R³ is selected from the group consisting of: H and Cl.

In another aspect, the present invention includes compounds of Formula(V): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a solvate, or a prodrug thereof, wherein:

ring B is selected from the group consisting of:

L is —CH₂-2,6-(3-F-pyridinylene)-(CH₂)₂—;

Y is selected from the group consisting of: CH₂ and —CONH—;

R³ is selected from the group consisting of: H and Cl; and

R^(6a) is selected from the group consisting of: H and —NHCO₂Me.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦10 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦1 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦0.5 μM.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values ≦0.1 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a second factor Xa inhibitor, an anti-coagulant agent, ananti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent,and a fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, dabigatran, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, desulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “Coalkyl” or “Co alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Hawley'sCondensed Chemical Dictionary (13th Ed.), Lewis, R. J., ed., J. Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Design of Prodrugs, Bundgaard, H., ed., Elsevier (1985), and Methodsin Enzymology, 112:309-396, Widder, K. et al., eds., Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, Medicinal Chemistry Principles and Practice, King, F. D., ed.The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); The Practiceof Medicinal Chemistry, Wermuth, C. G., ed., Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz carbobenzyloxy-   CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CDCl₃ chloroform-   mCPBA or m- meta-chloroperbenzoic acid-   CPBA-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)- (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5--   EtDuPhosRh(I) cyclooctadiene)rhodium(I) trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)    (triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl_(2 [)1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl)aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Imidazole derivatives useful for the synthesis of the compounds of thisinvention may be synthesized according to the general method outlined inScheme 1 (Contour-Galcera et al., Bioorg. Med. Chem. Lett.,11(5):741-745 (2001)). Alkylation of the potassium or cesium carboxylateof an appropriately protected or derivatized alpha amino acid 1a with asuitably substituted alpha-bromoketone 1b (ring C is aryl or heteroaryl)provides the keto ester 1c. The imidazole 1d is formed by heating theketo ester 1c to reflux in a suitable solvent, such as toluene orxylenes, in the presence of excess ammonium acetate using a Dean-Starktrap to remove water. Formation of the imidazole can also be carried outby combining the keto ester 1c and ammonium acetate in a suitablesolvent, such as xylene or ethanol or a combination of solvents such asdimethylformamide and ethanol (1:1) and using microwave heating.Imidazole 1d can then be protected with as suitable protecting group.For example, imidazole 1d can be reacted with SEM-Cl, in the presence ofbase, such as sodium hydride or dicyclohexylmethyl amine, and in asolvent such as dimethylformamide or tetrahydrofuran to give 1e.

Imidazole containing macrocycles of this invention wherein Y is —CH₂—can be prepared according to Scheme 2. Suzuki-Miyaura coupling between2a, prepared as described in Scheme 1, and a suitably substituted alkylboronic acid 2b in the presence of silver(I) oxide and a base, such aspotassium carbonate, using a precatalyst such as Pd(dppf)Cl₂.CH₂Cl₂complex, in a solvent such as tetrahydrofuran at elevated temperaturesprovides 2c (Falck, J. R., Tetrahedron Letters, 42:7213 (2001)). Using amodified procedure described by Lovely (Tetrahedron Letters, 44:1379(2003)), 2c, following pretreatment with p-toluenesulfonic acid to formthe imidazolium ion, can be cyclized via ring-closing metathesis using acatalyst, such as Grubbs (II), in a suitable solvent, such asdichloromethane, dichloroethane, or toluene at elevated temperature, togive the imidazole-containing macrocycle as a mixture of olefin isomers(E-alkene 2d and Z-alkene 2e). The olefins can be separated, and thendeprotection of both the Boc and SEM groups with aqueous 5M hydrochloricacid in methanol or ethanol at elevated temperature provides amines 2fand 2g. Alternatively, the deprotection can be performed under anhydrousconditions with 4M hydrochloric acid in dioxane at elevatedtemperatures. The mixture of olefin isomers (E-alkene 2d and Z-alkene2e) can be reduced with hydrogen over either palladium on carbon orplatinum oxide and subsequent deprotection as described above gives thesaturated amine 2h. Amide coupling between amines 2f-h, with anappropriately substituted carboxylic acid 2k, employing suitablecoupling reagents, such as EDCI, HOBt, and base generates 2m-o (foralternative coupling reagents see: Han, S.-Y. et al., Tetrahedron,60:2447 (2004)). Alternately, amines 2f-h can be coupled with anactivated carboxylic ester 21 in the presence of a base such as Hunig'sbase and in a solvent such as dimethylformamide to give 2m-o. Furtherfunctional group incorporation on the imidazole ring may be achieved bychlorination of the C-5 of the imidazole ring with N-chlorosuccinimide,using a suitable solvent such as methylene chloride, acetonitrile orchloroform to give compounds 2p-r. Further functional groupincorporation on the imidazole ring may also be achieved by fluorinationof the C-5 of the imidazole ring with Accufluor, using a suitablesolvent such as dimethylformamide in the presence of a base, such assodium carbonate.

Imidazole containing macrocycles of this invention wherein Y is NH,NHC(O), NHCO₂, NHC(O)NH, and NHSO₂ can be prepared according to Scheme3. Using a modified procedure described by Ma (Synthesis, 3:496 (2005)),bromide 2a can be coupled with an appropriately substituted amine 3aemploying copper (I) iodide and L-proline in the presence of a base suchas potassium carbonate, in a solvent such as dimethylsulfoxide atelevated temperature to give the substituted aniline 3g. Alternatively,bromide 2a can be converted to the unsubstituted aniline 3b undersimilar reaction conditions (Chang, S., Chem. Commun., 3052 (2008)). Theaniline 3b can then be coupled with an appropriately substitutedcarboxylic acid 3c using T3P in a solvent such as ethyl acetate ordimethylformamide to give the amide 3h. The aniline 3b can also becoupled with an appropriately substituted chloroformate 3d, isocyanate3e, or sulfonyl chloride 3f to provide the carbamate 3k, urea 31, andthe sulfonamide 3m, respectively. Compounds of the formula 3g, 3h, and3k-m can be converted to compounds 3n-r according to Scheme 2. For thepreparation of compounds of the formulae 3n, the preferred method forremoving both the Boc and SEM, as described in Scheme 2, employsanhydrous 4M hydrochloric acid in dioxane at elevated temperatures witheither cysteine or O-methyl hydroxylamine as a formaldehyde scavenger.

Imidazole-containing macrocycles of this invention wherein Y is C(O)NHcan be prepared according to Scheme 4. Subjecting 2a to methyllithiumfollowed by metal-halogen exchange with n-butyllithium and quenching theintermediate anion with carbon dioxide provides the carboxylic acid 4a.Amide coupling with an appropriately substituted amine 4b, as previouslydescribed for the conversion of 3b to 3h, gives amide 4c. Amide 4c canbe converted to compounds 4d-f according to Scheme 2.

Chiral amino acids 1a useful for the synthesis of imidazole compounds ofthis invention are either commercially available or can be prepared byany of a number of methods known in the art. For example, as shown inScheme 5, didehydroamino acid derivatives of formula 5a may be reducedto provide protected (S)-amino acids of formula 5b by hydrogenation inthe presence of a chiral catalyst such as (S,S)-EtDuPhosRh(I) using amodified procedure of Burk (J. Am. Chem. Soc., 113:8518 (1991)).Didehydroamino acid derivatives of formula 5a can be prepared viaseveral methods, such as for example, a Heck coupling between an aryliodide, bromide, or triflate of formula 5c and Boc didehydroalaninebenzyl ester, using a modified procedure of Carlström et al. (Synthesis,414 (1989)). Alternatively, protected didehydroaminoacids of formula 5amay be prepared by Horner-Emmons type condensation of an suitablysubstituted aldehyde of formula 5d withBoc-methyl-2-(dimethylphosphono)glycinate, using modifications ofliterature procedures (Wang et al., Tetrahedron, 58:3101 (2002)).Protected amino acids of formula 5b may also be prepared by alkylationof methyl 2-(diphenylmethyleneamino)acetate with an appropriatelysubstituted benzylbromide 5e in the presence of a chiral cinchonidiniumcatalyst in a suitable solvent, such as methylene chloride, using aprocedure similar to that described by O'Donnell et al. (Tetrahedron,55:6347 (1999)), followed by mild acidic workup and reprotection of theamino functionality with a Boc group according to methods known to oneskilled in the art. Substitution of heteroaryl bromides or iodides for5c, heteroaryl aldehydes for 5d, and heteroarylalkyl for 5e in Scheme 5would lead to additional chiral amino acids useful for the synthesis ofimidazole compounds of this invention.

Certain 2-bromoacetophenone analogs (1b, C=aryl) that are notcommercially available may be synthesized from commercially availablestarting materials as described in Scheme 6. Acetophenone derivatives 6acan be treated with a brominating reagent such as bromine in a solventsuch chloroform to give 6b. Alternatively, acetophenone derivatives 6acan be treated with either copper (II) bromide in a solvent such asethyl acetate at elevated temperature or phenyltrimethylammoniumtribromide in a solvent such as tetrahydrofuran at low temperature toprovide 6b. Benzoic acid derivatives 6c can be treated sequentially withoxalyl chloride in a suitable solvent, such as dichloromethane,containing a few drops of DMF, and then treated withtrimethylsilyldiazomethane in a suitable solvent or solvent combination,such as acetonitrile and hexane. The intermediate diazoketone isisolated and treated with aqueous hydrobromic acid and dichloromethaneto provide 6b. Alternatively the benzoic acid derivatives 6c can beconverted to the acetophenone derivatives 6a in three steps as describedin Scheme 6. Alternatively, Stille coupling between a suitablysubstituted aryl halide or triflate and tributyl-(1-ethoxyvinyl)stannane with a palladium catalyst, such asbis-(triphenylphosphine)palladium dichloride, in a suitable solvent,such as toluene, at elevated temperature yields the enol ether 6e. Theresulting enol ether 6e can be converted to 6b with N-bromosuccinimide.

The syntheses of appropriately substituted carboxylic acids of formulae2k, where A=aryl and where L₁=—CH₂CH₂—, —CH═CH—, —C≡C—, —OCH₂—,—S(O)_(p)CH₂—, or —CH₂NH—, useful for the synthesis of amide compoundsof this invention as outlined in Scheme 2 are described in PCTInternational Application No. WO 2009/114677 published Sep. 17, 2009,which is incorporated in its entirety herein by reference. In addition,1-amino-5,6,7,8-tetrahydroisoquinoline-6-carboxylic acid useful for thesynthesis of amide compounds of this invention as outlined in Scheme 2is described in U.S. Patent Application No. 2005/0282805 published Dec.22, 2005, which is incorporated in its entirety herein by reference.

Representative pyridine (ring B=pyridine) containing macrocycles of thisinvention wherein Y is NHCO can be prepared as shown in Scheme 7.Condensation of aldehyde 7a, prepared according to a modified proceduredescribed by Negi (Synthesis, 991 (1996)), with(S)-2-methylpropane-2-sulfinamide in the presence of anhydrous coppersulfate in a solvent such as dichloromethane gives the sulfinimine 7b(Ellman, J., J. Org. Chem., 64:1278 (1999)). Using a modified proceduredescribed by Kuduk (Tetrahedron Letters, 45:6641 (2004)), suitablysubstituted Grignard reagents, for example allylmagnesium bromide, canbe added to sulfinimine 7b to give a sulfinamide 7c, as a mixture ofdiastereomers which can be separated at various stages of the sequence.Suzuki-Miyaura coupling between 4-chloropyridine 7c and an appropriatelysubstituted aryl or heteroaryl boronic acid or ester 7d in the presenceof a base such as potassium phosphate in a solvent mixture, suchdimethylsulfoxide and water, or dimethylformamide, using a precatalystsuch as Pd(dppf)Cl₂.CH₂Cl₂ complex provides 7e. Protecting groupinterconversion can be accomplished in two steps to give 7f. The aniline7f can then be coupled with an appropriately substituted carboxylic acid3c using propane phosphonic acid anhydride (T3P) to give the amide 7g.Ring closing metathesis, as described previously in Scheme 2, affordsthe pyridine containing macrocycle 7h, as the E-alkene. Boc deprotectionon 7h with either TFA in dichloromethane or 4M hydrochloric acid indioxane gives amine 7k. Alternatively, hydrogenation of 7h followed byBoc deprotection with TFA in dichloromethane provides amine 71.Compounds 7k and 71 can be converted to compounds 3m and 3n according toScheme 2.

Additional pyridine (ring B=pyridine) containing macrocycles of thisinvention wherein Y is NHCO₂, NHC(O)NH, and NHSO₂ can be preparedaccording to Scheme 7 by replacing 3c with an appropriately substitutedchloroformate 3d, isocyanate 3e, or sulfonyl chloride 3E Additionalmacrocycles containing regioisomeric pyridine scaffolds to the onedescribed in Scheme 7 can be prepared by an analogous sequence.

Methods for synthesis of a large variety of substituted pyridinecompounds useful as starting materials for the preparation of compoundsof the present invention are well known in the art and have beenextensively reviewed. (For examples of methods useful for thepreparation of pyridine starting materials see: Kroehnke, F., Synthesis,1 (1976); “Pyridine and Its Derivatives”, The Chemistry of HeterocyclicCompounds, 14(Suppl. 1-4), Abramovitch, R. A., ed., John Wiley & Sons,New York (1974); Comprehensive Heterocyclic Chemistry, 2:165-524,Boulton, A. J. et al., eds., Pergamon Press, New York (1984);Comprehensive Heterocyclic Chemistry, 5:1-300, McKillop, A., ed.,Pergamon Press, New York (1996)).

In cases where suitably substituted boronic acids are not commerciallyavailable, a modification to this approach may be adopted wherein anaryl halide is subjected to a palladium mediated coupling with a diboronspecies such as bis(pinacolato)diboron or bis(neopentylglycolato)diboron to provide the corresponding4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the5,5-dimethyl-[1,3,2]dioxaborolane intermediates using the method ofIshiyama, T. et al. (J. Org. Chem., 60(23):7508-7510 (1995)).Alternately, this same intermediate can be prepared by reaction of theintermediate halide with the corresponding dialkoxyhydroborane asdescribed by Murata et al. (J. Org. Chem., 62(19):6458-6459 (1997)). Theboron pinacolate intermediates can be used in place of boronic acids forcoupling to the aryl/heteroaryl halides or triflates or the boronpinacolate intermediate can be converted to the boronic acids.Alternately, the corresponding boronic acids can be prepared bymetal-halogen exchange of the aryl/heteroaryl halide, quenching with atrialkoxyborate reagent, and aqueous workup to provide the boronic acids(Miyaura, N. et al., Chem. Rev., 95:2457 (1995)).

It is also realized that the scope of intermediate synthesis can befurther extended outside the use of Suzuki-Miyaura coupling methodologysince the precursor aryl halides or triflates described above are alsoprecursors for Stille, Negishi, Hiyama, and Kumada-type cross couplingmethodologies (Tsuji, J., Transition Metal Reagents and Catalysts:Innovations in Organic Synthesis, John Wiley & Sons (2000); Tsuji, J.,Palladium Reagents and Catalysts: Innovations in Organic Synthesis, JohnWiley & Sons (1996)).

Representative phenyl (ring B=phenyl) containing macrocycles of thisinvention wherein Y is NHCO can be prepared as shown in Scheme 8. Usinga modification of the procedure described by Hart (J. Org. Chem.,48(3):289-294 (1983)), in situ generation of N-trimethylsilylaldiminesfrom a suitably substituted benzaldehyde 8a and lithiumbis(trimethylsilyl)amide, followed by the addition of Grignard oralkyllithium reagents 8b, for instance allylmagnesium bromide, givesafter aqueous work up the amine 8c. The amine can be protected as theBoc. Compounds of the formula 8e and 8f can be prepared following thesequence described in Scheme 7, by replacing 7c with 8d.

Representative pyridazine (ring B=pyridazine) containing macrocycles ofthis invention wherein Y is NHCO can be prepared as shown in Scheme 9.Using a modification of the Minisci reaction described by Cowden (Org.Lett., 5:4497-4499 (2003)), an appropriately protected or derivatizedalpha amino acid 1a and 3,6-dichloropyridazine 9a can be coupled atelevated temperature in the presence of silver nitrate, ammoniumpersulfate, and an acid, such as trifluoroacetic acid, in a solvent,such as water or a water/dimethylformamide mixture, to give compounds ofthe formulae 9b. Compound 9b wherein R═H, prepared using anappropriately protected glycine derivative of 1a, can be furtherfunctionalized by deprotonation with sec-BuLi and subsequent alkylationwith an appropriately substituted alkyl halide, for instance allylbromide, to give compound 9c. Suzuki-Miyaura coupling betweenchloropyridazine 9c and an appropriately substituted aryl or heteroarylboronic acid or ester 7d in the presence of a base such as potassiumphosphate in a solvent mixture, such dimethylsulfoxide and water, ordimethylformamide, using a precatalyst such as Pd(dppf)Cl₂.CH₂Cl₂complex provides 9d. Compounds of the formula 9e and 9f can be preparedfollowing the sequence described in Scheme 7, by replacing 7f with 9d.

Methods for the synthesis of a large variety of substituted pyridazinesuseful for the preparation of compounds of the present invention arewell known in the art. (For examples of methods useful for thepreparation of pyridazine starting materials see: “Pyridazines”, TheChemistry of Heterocyclic Compounds, Vol. 28, Castle, R. N., ed., JohnWiley & Sons, New York (1973); “The Pyridazines”, The Chemistry ofHeterocyclic Compounds, 57(Suppl. 1), Brown, D. J., ed., John Wiley &Sons, New York (2000); Comprehensive Heterocyclic Chemistry II, 6:1-93,Boulton, A. J., ed., Elsevier Science Inc., New York (1996)).

Oxadiazole derivatives useful for the synthesis of the compounds of thisinvention may be synthesized according to the general method outlined inScheme 10. A suitably protected amino acid 1a is coupled to a hydrazideof formula 10a in the presence of a coupling reagent such as HATU or T3Pto provide acylhydrazide 10b which is cyclized to the correspondingoxadiazole 10c by heating in the presence of Burgess reagent in asuitable solvent such as THF.

Representative oxadiazole (ring B=oxadiazole) containing macrocycles ofthis invention wherein Y is NHCO can be prepared as shown in Scheme 10a.Thus from N-Boc-allylglycine and a suitably substituted2-nitrophenylhydrazine, compounds of formula 10d can be obtained andthen converted into macrocyclic compounds of this invention usingsimilar chemistry to that described above in Scheme 7.

It should be recognized to one skilled in the art of organic synthesisthat additional macrocyclic compounds of this invention can be preparedby alternative cyclization strategies which are not limited to thering-closing metathesis strategy described in Scheme 2. For instance,macrolactamization can also be used as described in Scheme 11. Slowaddition of a solution 11a and Hunig's base in DMF to a solution BOPreagent in a mixture dichloromethane and DMF, provides macrocycle 11b.Hydrogenolysis of the Cbz provides the amine 11c. Amide coupling of theamine 11c with 2k or 21, as described in Scheme 2, and globaldeprotection gives 11d.

Representative imidazole-containing macrocycles of this inventionwherein L containing a pyridine ring can be prepared according to Scheme12. The starting amino acid 12d can be prepared from either 12a or 12b.Bromination of 12a with NBS/AIBN, followed by addition of diethyl2-acetamidomalonate provides compound 12c. Decarboxylation of 12c,followed by Boc protection of the amino group, gives 12d. The amino acid12d can also be obtained from 12b by the procedures described in Scheme5, followed by hydrolysis. Compound 12d can be converted to theimidazole 12f via the procedures described in Scheme 1. Heck coupling of12f with methyl acrylate gives 12g. Hydrogenation of 12g provides 12h.Alternatively, 12h can be prepared from 12d by benzyl ester formation,followed by Heck coupling with methyl acrylate, hydrogenation, andamination described in Scheme 3. Hydrolysis of 12h, followed bymacrocyclization with BOP/DMAP/DIEA produces the macrocycle 12n.Deprotection of the Boc group with TFA and then following the proceduresdescribed in Scheme 2 gives compounds 12o and 12p.

Scheme 12 can also be applied to representative imidazole-containingmacrocycles of this invention wherein L containing a phenyl ring where Nis replaced by CH.

Representative imidazole-containing macrocycles of this inventionwherein L containing a pyrimidine ring can be prepared according toScheme 13 and then followed the same procedures described in Scheme 12.The key amino acid derivative 13g can be prepared from 13a. Heckcoupling of 13a with t-butyl acrylate gives 13c. Reduction of the methylester in 13c with LiBH₄ gives alcohol 13d, which can be oxidized toaldehyde 13e. Reaction of 13e with phosphoglycine followed the procedurein Scheme 5 produces 13f. Reduction of 13f with Duphos catalyst gives13g, which can be used to prepared the pyrimidine macrocycles followedthe procedures in Scheme 12.

Additional imidazole containing macrocycles of this invention wherein Yis NH can be prepared according to Scheme 14. Using a modified proceduredescribed by Ma (Synthesis, 3:496 (2005)), bromide 2a can be coupledwith an appropriately substituted amine or amino acid (R⁷═CO₂H) 14aemploying copper (I) iodide and L-proline in the presence of a base suchas potassium carbonate, in a solvent such as dimethylsulfoxide atelevated temperature, followed by alkylation of the carboxylic acidmoiety with an alkyl iodide such as methyl iodide, gives the substitutedaniline 14b. Alternatively, 14b can be prepared using a modifiedprocedure described by Zhao (Synthesis, 19:3189 (2006)). Combininganiline 3b with appropriately substituted aldehdydes 14c in the presenceof maleic acid and allyltributyltin provides 14b. Alternatively, aniline3b can be condensed with trifluoroacealdehyde ethyl hemiacetal followedby the addition of Grignard reagents, such as allylmagnesium bromide,which gives 14d. Compounds of the formula 14b and 14d can be convertedto compounds 14e and 14f according to Scheme 2. For the preparation ofcompounds of the formulae 14e and 14f, the preferred method for removingboth the Boc and SEM, as described in Scheme 2, employs anhydrous 4Mhydrochloric acid in dioxane at elevated temperatures with eithercysteine or O-methyl hydroxylamine as a formaldehyde scavenger. Furthermanipulation of functional groups on R⁷ using methods known to oneskilled in the art of organic synthesis will give additional compoundsof the invention.

Additional imidazole macrocycles of this invention wherein R³ is CN, canbe prepared according to Scheme 15. Deprotection of intermediates 15gand 15h followed by amide coupling as described above will then provideadditional compounds of this invention. Further manipulation offunctional groups at R⁷ and R³ using methods known to one skilled in theart of organic synthesis and as exemplified in the specific examplesgiven below will give additional compounds of the invention.

Additional imidazole containing macrocycles of this invention can beprepared according to Scheme 16. Regioselective protection of the2,4-dibromo imidazole with SEM-C1 provides 16b. Metal-halogen exchangeof 16b with n-BuLi followed by quenching with dimethylformamide affordsa mixture of the C2 and C4 aldehydes. Condensation of the C2-aldehydewith (S)-2-methylpropane-2-sulfinamide in the presence of anhydrouscopper sulfate in a solvent such as dichloromethane gives thesulfinimine 16c. Appropriately substituted Grignard reagents, forexample allylmagnesium bromide, can be added to sulfinimine 16c to givesulfinamine 16d, as a mixture of diastereomers which can be separated atvarious stages of the sequence. Alternatively, the 2,4,5-tribromoimidazole 16e can be converted to 16h according to the four stepsequence described above. Regioselective halogen-magnesium exchange of16h with isopropylmagnesium chloride, followed by quenching withsaturated ammonium chloride, provides 16d. Suzuki-Miyaura couplingbetween bromoimidazole 16d and an appropriately substituted aryl orheteroaryl boronic acid or ester 7d in the presence of a base such aspotassium carbonate in a solvent, such dioxane, using a catalyst such asPd(tBu₃P)₂ provides 16k. Protecting group interconversion can beaccomplished in two steps to give 3b. Compound 3b can be converted tocompound 3o according to Scheme 3.

Representative pyridone (ring B=pyridone) containing macrocycles of thisinvention can be prepared as shown in Scheme 17. Compound 17d can beprepared in two steps according to a modified procedure described byResmini (Resmini, M. et al., Tetrahedron Asymmetry, 15:1847 (2004)). Asuitably substituted amino ester 17a can be converted to thecorresponding β-ketophosphonate 17b by treatment with lithiumdimethylmethylphosphonate. Horner-Wadsworth-Emmons reaction of 17b and asuitably substituted aldehyde 17c in the presence of base such aspotassium carbonate in a solvent such as ethanol or tetrahydrofurangives the α,β-unsaturated ketone 17d. Condensation of 17d with1-(ethoxycarbonylmethyl)-pyrdinium chloride or1-(carbamoylmethyl)-pyridinium chloride in the presence of ammoniumacetate in a solvent such as ethanol or glacial acetic acid generatesthe pyridone 17e. The nitro group can be reduced to the aniline 17f withzinc and ammonium chloride in methanol. Alternatively, alkylation of thecesium salt of the pyridone 17e with methyl iodide, followed byreduction of the nitro as described above, can yield the N-Me pyridonederivative 17g. Compounds of the formula 17f and 17g can be converted tocompounds 17h-k, according to Scheme 7, or to compounds 171-m, accordingto Scheme 14.

Representative pyrimidine (ring B=pyrimidine) containing macrocycles ofthis invention can be prepared as shown in Scheme 18. Condensation ofthe β-ketoester 18b, prepared according to a modified procedure ofMaibaum (J. Org. Chem., 53:869 (1988)), with a suitably substitutedamidine under basic conditions, such as formamidine and sodium methoxidein methanol, yields the pyrimidone 18c. The pyrimidone can be convertedto the chloro pyrimidine 18d in two steps with phosphorus oxychlorideand then reprotection of the amine with Boc-anhydride. Alternatively,the pyrimidone can be converted directly to the corresponding triflate18e with sodium hydride and N-phenyltrifluoromethanesulfonimideSuzuki-Miyaura coupling between 18d or 18e and an appropriatelysubstituted aryl or heteroaryl boronic acid or ester 7d in the presenceof a base such as potassium phosphate in a solvent mixture, suchdimethylsulfoxide and water, or dimethylformamide, using a precatalystsuch as Pd(dppf)Cl₂.CH₂Cl₂ complex provides 18f. Compounds of theformula 18f can be converted to compounds 18g-h, according to Scheme 7,or to compounds 18i, according to Scheme 14.

Representative pyridazinone (ring B=pyridazinone) containing macrocyclesof this invention can be prepared as shown in Scheme 19. Condensation ofthe potassium salt of 17b with a suitably substituted α-ketoester 19a,which is either commercially available or prepared using a modifiedprocedure described by Domagala (Tetrahedron Lett., 21:4997-5000), in asolvent such as tetrahydrofuran generates the α,β-unsaturated ketonederivative which can then be condensed with a suitably substitutedhydrazine derivative to give pyridazinone 19b. The nitro group can bereduced to the aniline 19c with zinc and ammonium chloride in methanol.Compounds of the formula 19c can be converted to compounds 19d accordingto Scheme 14.

It should be recognized that additional deprotection steps and furtherfunctional group manipulations of compounds obtained via Schemes 1-19using methods known in the art will then provide additional compounds ofthis invention.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and ethyl acetate or dichloromethaneand methanol unless otherwise indicated. Reverse phase preparative HPLCwas carried out using C18 columns eluting with gradients of Solvent A(90% water, 10% methanol, 0.1% TFA) and Solvent B (10% water, 90%methanol, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (90%water, 10% acetonitrile, 0.1% TFA) and Solvent B (10% water, 90%acetonitrile, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (98%water, 2% acetonitrile, 0.05% TFA) and Solvent B (98% acetonitrile, 2%water, 0.05% TFA, UV 254 nm).

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC using the Waters SunFire column (3.5 μmC18, 3.0×150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent Bfor 12 min and then 100% Solvent B for 3 min was used. Solvent A is (95%water, 5% acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95%acetonitrile, 0.05% TFA, UV 254 nm). Method B: Agilent ZORBAX® (3.5 μmC18, 4.6×75 mm) eluted at 2.5 mL/min with an 8 min gradient from 100% Ato 100% B (A: 10% methanol, 89.9% water, 0.1% H₃PO₄; B: 10% water, 89.9%methanol, 0.1% H₃PO₄, UV 220 nm). Method C: Waters SunFire column (3.5μm C18, 4.6×150 mm) eluted at 1 mL/min with a gradient from 10-100%Solvent B for 10 min and then 100% Solvent B for 5 min. (A: 0.01 MNH₄HCO₃ in water:methanol 95:5. B: 0.01 M NH₄HCO₃ in water:methanol5:95. UV 254 nm). Method D: Waters SunFire column (3.5 μm C18, 3.0×150mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B for 10 min andthen 100% Solvent B for 5 min was used. Solvent A is (95% water, 5%acetonitrile, 0.05% TFA) and Solvent B is (5% water, 95% acetonitrile,0.05% TFA, UV 254 nm).

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, thrombosis in thecavity of the heart, ischemic stroke, deep vein thrombosis, peripheralocclusive arterial disease, transient ischemic attack, and pulmonaryembolism. In addition, thrombosis occurs on artificial surfaces incontact with blood, including catheters, stents, artificial heartvalves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Hemostasis andThrombosis, Basic Principles and Clinical Practice, 5th Ed., p. 853,Colman, R. W. et al., eds., Lippincott Williams & Wilkins (2006))

Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in factor V (also known as factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of factor XII leads to a conformational change in the factorXII molecule, thereby facilitating activation to proteolytic activefactor XII molecules (factor XIIa and factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand factor XI. Active plasma kallikrein further activates factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of factor XIIdeficient mice. More specifically, factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that factor XI is down-stream from factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role infactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000))

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001)). Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. J.Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human factor XI protect against baboonarterial—venous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of factor XIa is also disclosed in published U.S. PatentApplication No. 2004/0180855A1. Taken together, these studies suggestthat targeting factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997)). Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding factor XII.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N Engl. J. Med., 342:696-701 (2000)).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 mg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Proteolytic activation by factor XIIa atan internal I389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Plasma kallikrein cleavesHMWK to liberate bradykinin. Bradykinin release results in increase ofvascular permeability and vasodilation (for review, Coleman, R.,“Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122,Lippincott Williams & Wilkins (2001); Schmaier A. H., “ContactActivation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, 2nd Ed., pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule factor XIa inhibitors in rabbit and rat model of arterialthrombosis, at doses that preserved hemostasis. (Wong P. C. et al.,American Heart Association Scientific Sessions, Abstract No. 6118, Nov.12-15, 2006; Schumacher, W. et al., Journal of Thrombosis andHaemostasis, Vol. 3 (Suppl. 1):P1228 (2005); Schumacher, W. A. et al.,European Journal of Pharmacology, pp. 167-174 (2007)). Furthermore, itwas observed that in vitro prolongation of the aPTT by specific XIainhibitors is a good predictor of efficacy in our thrombosis models.Thus, the in vitro aPTT test can be used as a surrogate for efficacy invivo.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N Engl. J.Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722(2005)). Hence, the most common cancers associated with thrombosis inmen are prostate, colorectal, brain, and lung cancer, and in women arebreast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., British Journal ofSurgery, 88:913-930 (2001)).

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; J T Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX® or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;CHROMOGENIX®) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000. Determinations weremade using purified human Factor XIIa at a final concentration of 4 nM(American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 pM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX®) at aconcentration of 0.00008-0.0004 M. The K_(m) value used for calculationof K_(i) was 0.00005 to 0.00007 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. using the method of Lineweaver andBurk. Values of K_(i) were determined by allowing the protease to reactwith the substrate in the presence of the inhibitor. Reactions wereallowed to go for periods of 20-180 minutes (depending on the protease)and the velocities (rate of absorbance or fluorescence change versustime) were measured. The following relationships were used to calculateK_(i) values:

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; or

v _(s) /v _(o) =A+((B−A)/1+((IC₅₀/(I)_(n)))); and

K _(i)=IC₅₀/(1+S/K _(m)) for a competitive inhibitor

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay

conditions;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P=K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios >20are considered selective. Compounds with selectivity ratios >100 arepreferred, and compounds with selectivity ratios >500 are morepreferred.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5× or IC2×, the inhibitor concentration requiredto increase the clotting time by 50 or 100 percent, respectively. TheIC1.5× or IC2× is found by linear interpolation from relative clottingtime versus inhibitor concentration plots using inhibitor concentrationthat spans the IC1.5× or IC2×.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g.,rat, or rabbit). A compound is diluted into plasma beginning with a 10mM DMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (Sysmex, Dade-Behring, Illinois). Similarly, clotting times canbe determined from laboratory animal species or humans dosed withcompounds of the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ALEXIN®(Trinity Biotech, Ireland) or ACTIN® (Dade-Behring, Illinois) followingthe directions in the package insert. Plasma (0.05 mL) is warmed to 37°C. for 1 minute. ALEXIN® or ACTIN® (0.05 mL) is added to the plasma andincubated for an additional 2 to 5 minutes. Calcium chloride (25 mM,0.05 mL) is added to the reaction to initiate coagulation. The clottingtime is the time in seconds from the moment calcium chloride is addeduntil a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus, Dade-Behring, Illinois) following the directions in the packageinsert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (Ki values) of ≦10 μM (10000 nM)was observed. Table 1 below lists Factor XIa Ki values measured for thefollowing examples.

TABLE 1 Example No. Factor XIa Ki (nM) 1 2983 10 <5 86 2392 102 8.16 1108117 111 71 140 <5 142 145 143 1309 III-2  78 III-20 7428 III-21 107III-33 103

B. In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed.

The femoral artery, jugular vein and femoral vein are isolated andcatheterized. A saline-filled AV shunt device is connected between thefemoral arterial and the femoral venous cannulae. The AV shunt deviceconsists of an outer piece of tygon tubing (length=8 cm; internaldiameter=7.9 mm) and an inner piece of tubing (length=2.5 cm; internaldiameter=4.8 mm). The AV shunt also contains an 8-cm-long 2-0 silkthread (Ethicon, Somerville, N.J.). Blood flows from the femoral arteryvia the AV-shunt into the femoral vein. The exposure of flowing blood toa silk thread induces the formation of a significant thrombus. Fortyminutes later, the shunt is disconnected and the silk thread coveredwith thrombus is weighed. Test agents or vehicle will be given (i.v.,i.p., s.c., or orally) prior to the opening of the AV shunt. Thepercentage inhibition of thrombus formation is determined for eachtreatment group. The ID₅₀ values (dose that produces 50% inhibition ofthrombus formation) are estimated by a nonlinear least square regressionprogram using the Hill sigmoid E_(max) equation (DeltaGraph; SPSS Inc.,Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 100 milligrams per dosage unit,and the second anti-coagulant in an amount of about 1 to about 50milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 25 milligrams of thecompound of the present invention and about 50 to about 150 milligramsof the anti-platelet agent, preferably about 0.1 to about 1 milligramsof the compound of the present invention and about 1 to about 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 1 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolyic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phosphodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an anti-arrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(alliskerin) and vasopepsidase inhibitors, an antiarrythmic agentselected from IKur inhibitors, an anticoagulant selected from thrombininhibitors, antithrombin-III activators, heparin co-factor IIactivators, other factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, factor VIIainhibitors, factor IXa inhibitors, and factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastro-intestinal tract in use. Clopidogrelis an even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent and selective Factor XIa inhibitor of the presentinvention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.

Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

Intermediate 1 (E)-2,5-Dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate

The synthesis was described as Intermediate 1 in PCT InternationalApplication No. WO 2009/114677 published Sep. 17, 2009.

Intermediate 2 (E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acrylic acid

The synthesis was described as Intermediate 1B in PCT InternationalApplication No. WO 2009/114677 published Sep. 17, 2009.

Intermediate 3 (E)-3-(3-Chloro-2-fluoro-6-tetrazol-1-yl-phenyl)-acrylicacid 2,5-dioxopyrrolidin-1-yl ester

Intermediate 3A(E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid

The synthesis of Intermediate 3A was described as Intermediate 7 in PCTInternational Application No. WO 2009/114677 published Sep. 17, 2009.

Intermediate 3

To a slightly turbid mixture of Intermediate 3A (1.0 g, 3.72 mmol) inTHF (18.70 mL) and DMF (1.870 mL) was added1-hydroxypyrrolidine-2,5-dione (0.471 g, 4.09 mmol) and DIC (0.638 mL,4.09 mmol). The reaction was stirred at rt and a white precipitateformed overtime. The solid was collected by suction filtration andwashed with MeOH, water, MeOH, air-dried, and dried under vacuum to giveIntermediate 3 (0.98 g, 72.0% yield), as a white solid. MS (ESI) m/z:366.2 (M+H)⁺.

Intermediate 4 (E)-3-(2-Acetyl-5-chlorophenyl)acrylic acid

Intermediate 4A (E)-tert-Butyl 3-(2-acetyl-5-chlorophenyl)acrylate

To a degassed solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.0 g,4.28 mmol), tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate(1.255 mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon(0.456 g, 0.428 mmol) and palladium(II) acetate (0.096 g, 0.428 mmol).The reaction mixture was warmed to 100° C. After 16 h, the reaction wascooled to rt. The reaction was filtered and the solid was rinsed withDMF. The filtrate was diluted with EtOAc, washed with water (2×), brine,dried over sodium sulfate, filtered and concentrated. Purification bynormal phase chromatography afforded Intermediate 4A (0.760 g, 63%), asa brown oil. MS (ESI) m/z: 225.0 (M-C₄H₈+H)⁺.

Intermediate 4

A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50% TFA/DCM (2mL) was stirred at rt. After 1 h, the reaction was concentrated to giveIntermediate 4 (0.038 g, 100% yield) as a yellow solid. The material wasused without further purification. MS (ESI) m/z: 225.1 (M+H)⁺.

Intermediate 5 1-Amino-5,6,7,8-tetrahydroisoquinoline-6-carboxylic acid

The synthesis was described as Example 147, Part E in U.S. PatentApplication No. 2005/0282805 published Dec. 22, 2005.

Intermediate 6 2-Bromo-1-(2-(but-3-enyloxy)phenyl)ethanone

Intermediate 6A 1-(2-But-3-enyloxy-phenyl)-ethanone

To a white suspension of potassium carbonate (15.2 g, 110 mmol) inacetone (29.4 mL) was added 5-bromobut-1-ene (3.73 mL, 36.7 mmol) and1-(2-hydroxyphenyl)ethanone (4.42 mL, 36.7 mmol). The resultingoff-white suspension was warmed to reflux and stirred overnight. Thereaction was cooled to rt, filtered and the filtrate was concentrated.The residue was partitioned between water and EtOAc and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. Purification by normal phase chromatographygave 1.12 g (15%) of Intermediate 6A, as a dark purple oil. MS (ESI)m/z: 205.2 (M+H)⁺.

Intermediate 6

A suspension of Intermediate 6A (1.1153 g, 5.86 mmol) and copper (II)bromide (2.62 g, 11.73 mmol) in EtOAc (10.47 mL) was warmed to reflux.After 1 h, the suspension was cooled to rt, filtered, and the filtratewas concentrated to give a greenish-brown residue. The greenish-brownresidue was taken up in EtOAc (100 mL) and washed with water (2×100 mL).The organic layer was then washed with brine, dried over Na₂SO₄,filtered, and concentrated. Purification by normal phase chromatographygave 0.773 g (44%) of Intermediate 6, as a yellow oil. MS (ESI) m/z:271.1 (M+H)⁺.

Intermediate 7 Methyl 4-(2-bromoacetyl)-3-(but-3-enyloxy)phenylcarbamate

Intermediate 7A 1-(4-Amino-2-(but-3-enyloxy)phenyl)ethanone

A suspension of 1-(4-amino-2-hydroxyphenyl)ethanone (3 g, 19.85 mmol),4-bromobut-1-ene (6.04 mL, 59.5 mmol) and K₂CO₃ (16.46 g, 119 mmol) inacetone (30 mL) was heated in a sealed tube at 60° C. After 18 h,another 2 eq. of 4-bromobut-1-ene was added and the reaction was heatedat 60° C. for 18 h. This process was repeated one more time, and thereaction was cooled to rt, diluted with EtOAc, washed with water, brine,dried over sodium sulfate, filtered and concentrated. Purification bynormal phase chromatography afforded 1.055 g (14.24%) of Intermediate7A, as a yellow solid. MS (ESI) m/z: 206.0 (M+H)⁺.

Intermediate 7B Methyl 4-acetyl-3-(but-3-enyloxy)phenylcarbamate

To a cooled (0° C.), clear yellow solution of Intermediate 7A (1.055 g)in DCM (9.42 mL) and pyridine (0.252 mL, 3.11 mmol) was added dropwisemethyl chloroformate (0.230 mL, 2.97 mmol). The resulting yellowsuspension was stirred at 0° C. for 2 h. The reaction was partitionedbetween EtOAc/sat. sodium bicarbonate and the layers were separated. Theaqueous layer was extracted with EtOAc (1×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated to give a yellow solid. The solid was purified bytrituration from DCM. The solid was collected via Buchner funnelfiltration and rinsed with DCM (3×2 mL), air-dried, and dried undervacuum to give 0.91 g of Intermediate 7B as a white solid. MS (ESI) m/z:264.0 (M+H)⁺.

Intermediate 7 was prepared following the procedure described inIntermediate 6, by replacing Intermediate 6A with Intermediate 7B. Thematerial was used without further purification. MS (ESI) m/z: 341.9(M+H)⁺ and 343.9 (M+2+H)⁺.

Intermediate 8 [3-Bromo-4-(2-bromo-acetyl)-phenyl]-carbamic acid methylester

Intermediate 8A

1-(4-Amino-2-bromophenyl)ethanone: (Caution, possible explosion hazard!)A clear, colorless solution of 1-(2-bromo-4-fluorophenyl)ethanone (22.8g, 0.105 mol) in DMSO (105 mL) and ammonium hydroxide (68.2 mL, 0.526mol) was divided into nineteen 20-mL microwave vials. The vials weresealed, microwaved at 150° C. for 1.5 h, and then cooled to rt. All thereactions were combined, partitioned between DCM and water (400 mL) andthe layers were separated. The aqueous layer was extracted with DCM(2×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated to give 35 g of Intermediate8A as an orange oil. The material was carried onto the next step withoutfurther purification. MS (ESI) m/z: 212.4 (M+H)⁺ and 214.4 (M+2+H)⁺.

Intermediate 8 was prepared following the procedures described inIntermediate 7, by replacing Intermediate 7A with Intermediate 8A. MS(ESI) m/z: 352.1 (M+H)⁺ and 354.1 (M+2+H)⁺.

An alternative preparation of Intermediate 8 is highlighted below:

Alternative Intermediate 8A 1-(4-Amino-2-bromophenyl)ethanone

To a solution of Intermediate 10C (19 g, 0.077 mol) in ethanol (400 mL)was added in portions tin(II) chloride (74 g, 0.39 mol). Following theaddition, the reaction was heated to reflux overnight. The reaction wasconcentrated and the residue was dissolved in 10% aq. sodium hydroxide(200 mL). The solution was extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with brine and concentrated toafford an oil. Petroleum ether (25 mL) was added to give a suspension.The petroleum ether was decanted and the solid was suspended in 20%ethyl acetate/petroleum ether. The solid was collected to afford 14 g ofIntermediate 8A.

Alternative Intermediate 8B (4-Acetyl-3-bromo-phenyl)-carbamic acidmethyl ester

To a cooled (10° C.) mixture of alternative Intermediate 8A (14 g, 0.065mol) and Hunig's base (12.7 g, 0.098 mol) in dry dioxane (140 mL) wasadded dropwise methyl chloroformate (7.4 g, 0.078 m). After 3 h, thereaction was quenched with water (100 mL) and then extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated. Purification bytrituration from isopropanol provided 14 g of the alternativeIntermediate 8B. MS (ESI) m/z: 271.7 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆)δ: 2.50 (s, 3H), 3.71 (s, 3H), 7.53-7.56 (m, 1H), 7.78 (d, J=8.8 Hz,1H), 7.86 (d, J=2.0 Hz, 1H), 10.14 (s, 1H).

Alternative Intermediate 8

To a cooled (10° C.) solution of alternative Intermediate 8B (90 g, 0.33mol) in dry dioxane (900 mL) was added a solution of bromine (52.9 g,0.33 mol) in dioxane (430 mL) dropwise over 1 h. After 2 h, ice coldwater (500 mL) was added and the reaction was extracted with ethylacetate (2×500 mL). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated to afford 110 g ofcrude product. A suspension of the crude product in ethanol (1 L) waswarmed to 50° C. After a clear solution formed, water (1.0 L) was addeddropwise and the mixture was gradually cooled to 35° C. The precipitatedsolid was collected by filtration, washed with ethanol (200 mL),air-dried, and then dried at 50° C. under vacuum for 30 min to yield 70g of alternative Intermediate 8.

Intermediate 9 Methyl 4-(2-bromoacetyl)-3-nitrophenylcarbamate

Intermediate 9A Methyl 4-iodo-3-nitrophenylcarbamate

To a cooled (0° C.), yellow suspension of 4-iodo-3-nitroaniline (8.46 g,32.0 mmol) in DCM (320 mL) and pyridine (2.85 mL, 35.2 mmol) was addeddropwise methyl chloroformate (2.61 mL, 33.6 mmol). The resulting clear,light yellow solution was stirred at 0° C. After 1.5 h, the reaction wasdiluted with DCM, washed with sat. NaHCO₃, brine, dried over MgSO₄,filtered and concentrated. The residue was dissolved in a minimal amountof DCM (˜100 mL) and then hexane (600 mL) was added to give a yellowsuspension. The suspension was filtered, and the solid was rinsed withhexane and then dried to give Intermediate 9A (10.3 g, 100%), as yellowsolid. MS (ESI) m/z: 321.3 (M−H)⁻.

Intermediate 9B Methyl 4-(1-ethoxyvinyl)-3-nitrophenylcarbamate

A solution of Intermediate 9A (6 g, 18.63 mmol),tributyl(1-ethoxyvinyl)stannane (7.55 mL, 22.36 mmol), andbis(triphenylphosphine)palladium(II) chloride (0.654 g, 0.932 mmol) intoluene (37.3 mL) was heated at 110° C. After 2 h, the reaction wascooled to rt. The reaction mixture was filtered through a 0.45 micronGMF, rinsing with EtOAc. The filtrate was concentrated. Purification bynormal phase chromatography gave Intermediate 9B (3.59 g, 72.4% yield),as a brown solid. MS (ESI) m/z: 267.4 (M+H)⁺.

Intermediate 9

To a slightly cloudy orange mixture of Intermediate 9B (3.59 g, 13.48mmol) in THF (20 mL) and water (7 mL) was added NBS (2.400 g, 13.48mmol). The resulting clear, yellow solution was stirred at rt for 20 minand then the reaction was partitioned between EtOAc/brine. The layerswere separated and the organic layer washed with brine, dried overNa₂SO₄, filtered, and concentrated to afford Intermediate 9 (4.28 g,100% yield), as a yellow foam. This material was used without furtherpurification. MS (ESI) m/z: 317.3 (M+H)⁺, 319.3 (M+2+H)⁺.

Alternatively, Intermediate 9B can be hydrolyzed with aqueous 1N HCl togive the methyl ketone which can then be brominated with copper (II)bromide according to the procedure described in Intermediate 6.

Intermediate 10 2-Bromo-1-(2-bromo-4-nitrophenyl)ethanone

Intermediate 10A 2-Bromo-4-nitro-benzoic acid

To a warm (80° C.) solution of pyridine (500 mL) and water (1.0 L) wasadded 4-nitro-2-bromo toluene (100 g, 0.46 mol). The resultingsuspension was stirred until it became a clear solution. Next, KMnO₄(600 g, 3.8 mol) was added in portions over 1.5 h. The reaction wasstirred overnight. The reaction mixture was cooled to RT and then 10%aq. sodium hydroxide (200 mL) was added. After 15 min, the reaction wasfiltered to remove the solid. The solid was rinsed with 10% aq. sodiumhydroxide (5×100 mL). The filtrate was extracted with MTBE (3×250 mL).The clear aqueous layer was cooled to 10° C. and then it was acidifiedwith concentrated HCl. The aqueous layer was extracted with MTBE (4×500mL). The organic layers were combined, dried over sodium sulfate,filtered and concentrated to afford 72 g of Intermediate 10A. ¹H NMR(400 MHz, DMSO-d₆) δ: 7.96 (d, J=8 Hz, 1H), 8.28-8.48 (m, 1H), 8.49 (d,J=2.4 Hz, 1H), 14.1 (br. s, 1H).

Intermediate 10B 2-(2-Bromo-4-nitro-benzoyl)-malonic acid diethyl ester

To a solution of Intermediate 10A (50 g, 0.2 mol) in toluene (500 mL)was added triethylamine (24.6 g, 0.24 mol). The reaction was cooled to15° C. and ethyl chloroformate (24 g, 0.22 mol) was added. After 45 min,the mixed anhydride solution was cooled to 0° C.

In a separate flask: To a suspension of Mg turnings (5.4 g) in dry ether(300 mL) was added ethanol (3.0 mL), carbon tetrachloride (2.0 mL), anddiethyl malonate (34 mL, 0.22 mol). The mixture was stirred at 40° C.for an hour to ensure that the magnesium dissolved completely. After thereaction became a clear solution, it was added to the cooled solution ofthe mixed anhydride. After 2 h, the reaction was quenched with 2Nsulfuric acid (200 mL) and then extracted with ethyl acetate (4×100 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated to give 80 g of Intermediate 10B. This was used in the nextstep without further purification.

Intermediate 10C 1-(2-Bromo-4-nitro-phenyl)-ethanone

A mixture of Intermediate 10B (80 g, 0.2 mol) in acetic acid (400 mL)and sulfuric acid (400 mL) was stirred at 105° C. After 3 h, thereaction was cooled to RT and then extracted with ethyl acetate (2×500mL). The combined organic layers were washed with 20% aq. sodiumhydroxide, dried over sodium sulfate, filtered and concentrated to give43.0 g of Intermediate 10C. ¹H NMR (400 MHz, CDCl₃) δ: 2.66 (s, 3H),7.57 (d, J=8 Hz, 1H), 8.21-8.24 (dd, 1H), 8.48 (d, J=2.0 Hz, 1H).

Intermediate 10

To a cooled (10° C.) solution of the Intermediate 10C (43 g, 0.17 mol)in dry dioxane (430 mL) was added a dropwise over 1.5 h a solution ofbromine (31 g) in dioxane (430 mL). The reaction was stirred for 30 minand then ice cold water (150 mL) was added. The reaction was extractedwith ethyl acetate (2×200 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated.Purification by normal phase chromatography (petroleum ether/ethylacetate) gave 30 g of Intermediate 10. ¹H NMR (400 MHz, CDCl₃) δ 4.46(s, 2H), 7.62 (d, J=8.4 Hz, 1H), 8.25-8.27 (dd, 1H), 8.50 (d, J=2.4 Hz,1H).

Intermediate 11 Methyl4-(2-bromoacetyl)-3-(pent-4-enyloxy)phenylcarbamate

This compound was prepared following the procedures described inIntermediate 7, by replacing 4-bromobut-1-ene with 5-bromopent-1-ene. MS(ESI) m/z: 355.9 (M+H)⁺, 357.9 (M+2+H)⁺.

Intermediate 122-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitro-phenylamine

To a flame-dried flask, equipped with a reflux condensor, containing2-bromo-5-nitroaniline (10.0 g, 46.1 mmol), bis(neopentylglycolato)diboron (13.01 g, 57.6 mmol), potassium acetate (13.57 g, 138mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (0.941 g, 1.152 mmol) was addedDMSO (132 mL). The resulting dark red-brown suspension was degassed withargon for 30 min. and then the reaction was warmed to 80° C. After 4 h,the reaction was stopped and cooled to rt. The reaction was pouredslowly into vigorously stirred ice-cold water (300 mL) to give a brownsuspension. After stirring for 10 min, the suspension was filtered tocollect the solid. The solid was rinsed with water (3×125 mL),air-dried, and then dried under a vacuum to give a brown solid.Purification by normal phase chromatography gave 4.36 g of Intermediate12 as an orange solid. MS (ESI) m/z: 183.1 (M−C₅H₈+H)⁺.

Intermediate 134-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester

Intermediate 13A4-Bromo-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoic acidmethyl ester

To a solution of methyl 4-bromo-3-hydroxybenzoate (2.0 g, 8.66 mmol) and2-(2-bromoethyl)isoindoline-1,3-dione (2.419 g, 9.52 mmol) in DMF (10mL) was added NaH (0.866 g, 21.64 mmol) in small portions at 0° C. Thereaction was stirred under argon at 0° C. for 2 h. The reaction waswarmed to 60° C. and stirred for 4 h. After cooling to rt, the reactionmixture was diluted with EtOAc, washed with 1M HCl, saturated NaHCO₃ andbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. Purification by normal phase chromatography gaveIntermediate 13A (0.36 g, 10.3% yield) as a white solid. MS (ESI) m/z:404.0/406.0 (M+H)⁺.

Intermediate 13 was prepared following the procedure described inIntermediate 12, by replacing 2-bromo-5-nitroaniline with Intermediate13A and running the reaction in acetonitrile at 90° C. MS (ESI) m/z:352.1 (M+H)⁺.

Intermediate 14[3-[(Benzyloxycarbonyl-methyl-amino)-methyl]-4-(2-bromo-acetyl)-phenyl]-carbamicacid methyl ester

Intermediate 14A Benzyl 5-amino-2-bromobenzyl(methyl)carbamate

To a mixture of benzyl 2-bromo-5-nitrobenzyl(methyl)carbamate (3.0 g,7.91 mmol) in MeOH (60 mL) was added ammonium chloride (2.116 g, 39.6mmol) and zinc (2.59 g, 39.6 mmol) at 0° C. The reaction mixture waswarmed up to rt and stirred under argon for 3 h. The solid was filteredoff and the solvent was removed to give Intermediate 14A (2.72 g, 98%yield) as a light tan solid. MS (ESI) m/z: 350.8 (M+H)⁺.

Intermediate 14 was prepared following the procedures described inIntermediate 9, by replacing 4-iodo-3-nitroaniline with Intermediate14A. MS (ESI) m/z: 449.0 (M+H)⁺.

Intermediate 15 (E)-3-(3-Chloro-2,6-difluoro-phenyl)-acrylic acid

Intermediate 15A 3-Chloro-2,6-difluorobenzaldehyde

To a solution of (3-chloro-2,6-difluorophenyl)methanol (1.07 g, 5.99mmol) in CH₂Cl₂ (20 ml) was added Dess-Martin periodinane (3.05 g, 7.19mmol). After 2 h, the reaction was concentrated. Purification by normalphase chromatography gave Intermediate 15A (0.94 g, 89% yield), as awhite solid. MS (ESI) m/z: 177.1 (M+H)⁺.

Intermediate 15B (E)-tert-Butyl 3-(3-chloro-2,6-difluorophenyl)acrylate

To a solution of Intermediate 15A (0.94 g, 5.32 mmol) in THF (30 ml)were added tert-butyl 2-(dimethoxyphosphoryl)acetate (1.194 g, 5.32mmol) and KOtBu (0.896 g, 7.99 mmol). After 2 h, the reaction wasdiluted with EtOAc, washed with H₂O, brine, dried over MgSO₄, filteredand concentrated. Purification by normal phase chromatography providedIntermediate 15B (0.866 g, 59.2% yield), as a clear colorless oil. MS(ESI) m/z: 219.2 (M-^(t)Bu+H)⁺.

Intermediate 15

To a solution of Intermediate 15B (0.866 g, 3.15 mmol) in DCM (7.0 ml)was added TFA (3.0 mL, 38.9 mmol). After 1.5 h, the reaction wasconcentrated and the residue was dried in vacuo to give Intermediate 15(0.689 g, 100% yield) as an off-white solid. MS (ESI) m/z: 219.1 (M+H)⁺.

Intermediate 16 3-[2-Amino-2-(4-chloro-pyridin-2-yl)-ethyl]-benzoic acidmethyl ester, 2 TFA salt

Intermediate 16A 4-Chloro-pyridine-2-carbonyl chloride

To a suspension of 4-chloro-pyridine-2-carboxylic acid (2.0 g, 12.8mmol) in dichloroethane (43 mL) was added thionyl chloride (2.8 mL, 38.5mmol) and DMF (2-3 drops). The suspension was warmed to 85° C. After 1h, the resulting clear, yellow solution was cooled to rt andconcentrated. The residue was dissolved in DCE and concentrated. Thisprocess was repeated two additional times to give a yellow liquid whichcrystallized upon standing to give a yellow solid.

Intermediate 16B 3-[2-(4-Chloro-pyridin-2-yl)-2-oxo-ethyl]-benzoic acidmethyl ester

(Preparation of the benzyl zinc reagent) To a flame-dried flask wasadded zinc powder (100 mesh, 0.570 g, 8.73 mmol). The flask was equippedwith a condenser and the system was purged with argon for severalminutes. Next, THF (1.75 mL) was added followed by 1,2-dibromoethane(0.075 mL, 0.87 mmol). The suspension was heated with a heat gun until agentle bubbling was observed and the reaction was allowed to cool to rt.The above process was repeated twice. Next, TMS-Cl (0.089 mL, 0.698mmol) was added and an exotherm was observed with bubbling. After 2 min,the zinc suspension was cooled to 0-5° C. Next, a solution of3-bromomethyl-benzoic acid methyl ester (1.0 g, 4.36 mmol) in THF (4.4mL) was added dropwise via syringe pump over 1 h and 45 min.(approximate rate of one drop every 6-8 sec) keeping the temperaturebelow 5° C. Following the addition, the stirring was stopped and thezinc was allowed to settle. After 1.5 h, the supernatant was used in thenext step.

To a cooled (−9° C.), solution of Intermediate 16A (0.767 g, 4.36 mmol)in THF (4.4 mL) was added dropwise the benzyl zinc reagent preparedabove keeping the temperature below 5° C. during the addition. To theresulting orange solution was addedtetrakis(triphenylphosphine)palladium(0) (0.126 g, 0.109 mmol) and thereaction temperature increase to 19° C. but subsided to 0-5° C. and thereaction was maintained in this temperature range. After 45 min, thereaction was quenched with 1.0 M HCl (15 mL) and then extracted withEtOAc (3×). The combined organic layers were washed with sat. sodiumbicarbonate, brine, dried over sodium sulfate, filtered and concentratedto give an orange residue weighing 1.28 g. Purification by normal phasechromatography gave 0.646 g (51%) of Intermediate 16B, as a yellow, oilysolid. MS (ESI) m/z: 290.20 (M+H)⁺ and 292.20 (M+2+H)⁺.

Intermediate 16

To an orange-yellow suspension of Intermediate 16B (0.570 g, 1.97 mmol)in methanol (7.9 mL) was added hydroxylamine hydrochloride (0.411 g,5.91 mmol). After 16.5 h, the reaction was concentrated and then theresidue was partitioned between EtOAc and sat. sodium bicarbonate. Thelayers were separated and the aqueous layer was extracted with EtOAc(1×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated to give 0.536 g of the oxime,as a yellow solid. To a cooled (0-5° C.) solution of oxime in TFA (4.5mL) was added in portions zinc powder (one portion every 10 min, 0.620g, 9.5 mmol). The reaction was allowed to warm to 15° C. and additionalTFA (4.5 mL) was added to facilitate mixing. After 4.5 h, the reactionwas filtered to remove the zinc, rinsing with TFA, and the resultingfiltrate was concentrated to remove most of the TFA. The mixture wasadded dropwise to cold (0° C.) 1.0 M sodium hydroxide. The mixture wasextracted with EtOAc (2×). The combined organic layers were filtered toremove the emulsion and then the filtrate was washed with brine, driedover sodium sulfate, filtered and concentrated to give an orangeresidue. Purification by reverse phase chromatography gave 0.409 g (39%)of Intermediate 16, as an off-white foam. MS (ESI) m/z: 291.2 (M+H)⁺ and293.2 (M+2+H)⁺.

Intermediate 17 2-Bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone

The synthesis was described as Method A-1, Page 92 in PCT InternationalApplication No. WO 2005/014566 published Feb. 17, 2005.

Intermediate 18 (E)-3-(6-Acetyl-3-chloro-2-fluoro-phenyl)-acrylic acid

Intermediate 18A 2-Bromo-4-chloro-3-fluorobenzoic acid

To a cooled (−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF wasadded dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture wasstirred at −30° C. for 30 min. Again the reaction mixture was cooled to−78° C., and a solution of 4-chloro-3-fluorobenzoic acid (25 g, 143mmol) in THF was added over 1 h. The reaction was stirred at −78° C.overnight. The next day a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was addedand the reaction was stirred at −78° C. for further 2 h and then RT for4 h. The reaction mixture was quenched with water, the layers wereseparated, and the aqueous layer washed with Et₂O. The aqueous layer wasacidified with 1.5N HCl and then extracted in EtOAc (2×200 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to afford Intermediate 18A (30 g, 83.3%). MS (ESI) m/z:252.6 (M−H)⁺.

Intermediate 18B Diethyl 2-((2-bromo-4-chloro-3-fluorophenyl)(hydroxy)methylene)malonate

To a suspension of Intermediate 18A (14.6 g, 57 mmol) in DCM (200 mL)was added thionyl chloride (6.6 mL, 88 mmol). The mixture was stirred atreflux for 3 h. The solvent was removed and the residue was dried invacuum to give the acid chloride as a light brown solid.

To a cooled (0° C.) suspension of sodium hydride (3.66 g (60%), 91.5mmol) in THF was added a solution of diethyl malonate (0.612 g, 3.82mmol) in THF (5 mL). After 10 min, a solution of the acid chloride (16.4g, 60 mmol) in THF (160 mL) was added slowly. Following the addition,the reaction was warmed to RT. After 30 min, the solvent was removed andthe residue was treated with cold (0° C.) 1.2 M HCl (150 mL). Themixture was extracted with EtOAc (3×250 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive Intermediate 18B (20 g, 87%) as a solid. MS (ESI) m/z: 395/397(M+H)⁺.

Intermediate 18C 1-(2-Bromo-4-chloro-3-fluorophenyl)ethanone

A solution of Intermediate 18B (18.6 g, 47 mmol) in acetic acid (200mL), H₂O (150 mL) and H₂SO₄ (2.0 mL) was stirred at 110° C. for 4 h.Most of the solvent was removed and the residue was diluted with EtOAc(400 mL), washed with water (5×20 mL), saturated NaHCO₃, 1N NaOH, andbrine. The solvent was removed to give Intermediate 18C (10 g, 84%) as alow melting solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.42 (q, J=6.8, 6.4 Hz,1H), 7.24 (q, J=6.4, 5.2 Hz, 1H), 2.5 (s, 3H).

Intermediate 18D (E)-tert-Butyl3-(6-acetyl-3-chloro-2-fluorophenyl)acrylate

To the mixture of Intermediate 18C (50 g, 198 mmol), tert-butyl acrylate(50.9 g, 397 mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was addedPd(OAc)₂ (8.9 g, 39.7 mmol). The resulting mixture was stirred at 90° C.overnight. The reaction was cooled to RT, filtered, and the filtrate wasconcentrated. Purification by normal phase chromatography gaveIntermediate 18D (30 g, 50.8%) as a light yellow solid. MS (ESI) m/z:242.7 (M+H)⁺.

Intermediate 18

A solution of Intermediate 18D (25 g, 84 mmol) in DCM (330 mL) and TFA(330 mL) was stirred at RT. After 1.5 h, the solvent was concentrated togive Intermediate 18 (19.5 g, 97.0) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ: 12.69 (bs, 1H), 7.80-7.76 (m, 2H), 7.62 (d, J=12.1 Hz, 1H),6.30 (dd, J=2.4, 2.0 Hz, 1H), 2.6 (s, 3H). MS (ESI) m/z: 241 (M−H)⁺.

Intermediate 19 (E)-3-(5-Chloro-2-(difluoromethyl)phenyl)acrylic acid

Intermediate 19A 2-Bromo-4-chloro-1-(difluoromethyl)benzene

To a solution of 2-bromo-4-chlorobenzaldehyde (1 g, 4.56 mmol) in DCM(15 mL) was added DAST (0.903 mL, 6.83 mmol) at 0° C. The reaction wasallowed to warm to rt and stir overnight. The reaction mixture wasdiluted with EtOAc, washed with sat NaHCO₃ and brine. The organic phasewas dried over magnesium sulfate, filtered and concentrated to giveIntermediate 19A (0.88 g. 80% yield) as a clear oil. MS (ESI) m/z: 261.2(M+Na)⁺.

Intermediate 19B (E)-tert-Butyl3-(5-chloro-2-(difluoromethyl)phenyl)acrylate

To a solution of Intermediate 19A (0.88 g, 3.64 mmol) in DMF (10 mL) wasadded tert-butyl acrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11mmol) and palladium acetate (0.082 g, 0.364 mmol). The reaction waswarmed to 90° C. After 5 h, the reaction was cooled to rt and thenfiltered to remove the solid. The filtrate was diluted with EtOAc,washed with 1M HCl, sat NaHCO₃ and brine. The organic phase was driedover magnesium sulfate, filtered and concentrated. Purification bynormal phase chromatography gave Intermediate 19B (232 mg, 22% yield) asa tan oil. MS (ESI) m/z: 233.1(M−tBu)⁺.

Intermediate 19

A solution of Intermediate 19B (232 mg, 0.804 mmol) in DCM (2.0 mL) wasadded TFA (2.0 mL, 26.0 mmol). The reaction was stirred under argon atrt. After 1 h, the solvent was removed and the residue was dried to giveIntermediate 19 (191 mg, 100% yield) as tan solid. ¹H NMR (400 MHz,CD₃OD) δ 7.99 (dt, J=15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=8.3 Hz,1H), 7.55-7.48 (m, 1H), 7.01 (t, J=54.6 Hz, 1H), 6.51 (d, J=15.8 Hz,1H). ¹⁹F NMR (376 MHz, CD₃OD) δ-111.67 (s, 2F). MS (ESI) m/z:233.1(M+H)⁺.

Intermediate 24 (E)-3-(5-Chloro-2-difluoromethoxy-phenyl)-acrylic acid

Intermediate 24A (E)-3-(5-Chloro-2-difluoromethoxy-phenyl)-acrylic acidtert-butyl ester

To a cooled (0° C.) solution of potassium tert-butoxide (0.407 g, 3.63mmol) in THF (10 mL) was added tert-butyl 2-(dimethoxyphosphoryl)acetate(0.528 mL, 2.66 mmol) and 5-chloro-2-(difluoromethoxy)benzaldehyde (0.50g, 2.420 mmol). The reaction was allowed to warm to RT. After 4 h, thereaction was quenched with the addition of sat. ammonium chloride. Thereaction was diluted with EtOAc, washed with sat. ammonium chloride, satNaHCO₃ and brine. The organic layer was dried over sodium sulfate,filtered and concentrated. Purification by normal phase chromatographygave 550 mg (74%) of Intermediate 24A as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.77 (1H, d, J=16.31 Hz), 7.58 (1H, d, J=2.51 Hz), 7.31(1H, dd, J=8.66, 2.64 Hz), 7.12 (1H, d, J=8.78 Hz), 6.52 (1H, t, J=72.78Hz) 6.40 (1H, d, J=16.31 Hz), 1.53 (9H, s). ¹⁹F NMR (376 MHz, CDCl₃) δppm −81.11. MS (ESI) m/z: 327.0 (M+Na)⁺.

Intermediate 24

To a solution of Intermediate 24A (458 mg, 1.503 mmol) in DCM (4.0 mL)was added TFA (2.0 mL, 26.0 mmol). The reaction was stirred under argonat RT for 1 h. The solvent was removed to give Intermediate 24 as awhite solid. MS (ESI) m/z: 249.0 (M+H)⁺.

Intermediate 25 3-(5-Chloro-2-tetrazol-1-yl-phenyl)-propionic acid

The synthesis was described as Example 63A in PCT InternationalApplication No. WO 2007/070826 published Jun. 21, 2007.

Intermediate 40(E)-3-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)acrylic acid

Intermediate 40 was prepared following the procedures described inIntermediate 24, by replacing 5-chloro-2-(difluoromethoxy)benzaldehydewith 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde. MS (ESI) m/z:292 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (1H, dd, J=16.17, 2.02Hz), 7.49-7.62 (2H, m), 6.67 (1H, dd, J=16.30, 1.39 Hz).

Example 1(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N-(E)-(S)-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl-acrylamide,1 TFA salt

1A. (S)-2-tert-Butoxycarbonylamino-pent-4-enoic acid2-(2-but-3-enyloxy-phenyl)-2-oxo-ethyl ester: A suspension of(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (515 mg, 2.394 mmol)and potassium hydrogen carbonate (0.288 g, 2.87 mmol) in DMF (12.00 mL)was stirred at rt for 20 min. The reaction was then cooled to 0° C. andIntermediate 6 (0.773 g, 2.87 mmol) was added. The resulting yellowsolution was allowed to warm to rt. After stirring overnight, thereaction was cooled to 0° C. and then poured into cold water to give awhite suspension. The white suspension was then extracted with EtOAc(3×75 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to give 1.072 g of 1A as ayellow oil. This was used without further purification. MS (ESI) m/z:304.3 (M−C₅H₈O₂+H)⁺.

1B.{(S)-1-[4-(2-But-3-enyloxy-phenyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: Compound 1A (1.07 g, 2.66 mmol) was dissolved inxylene (26.6 mL) and divided evenly between two 20-mL microwave vials.Next ammonium acetate (2.047 g, 26.6 mmol) was added to each vial. Thevials were microwaved at 140° C. for 30 min. The resulting bright orangesolutions were combined, partitioned between EtOAc and sat. NaHCO₃ andthe layers were separated. The aqueous layer was extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated to give a peach residue.Purification by normal phase chromatography gave 0.626 g (62%) of 1B asa sticky, yellow solid. MS (ESI) m/z: 384.4(M+H)⁺.

1C.{(S)-1-[4-(2-But-3-enyloxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a cooled (0° C.) suspension of NaH (58.7 mg,1.468 mmol) in DMF (2.06 mL) was added dropwise a solution of 1B (536.2mg, 1.40 mmol) in DMF (1.3 mL). The resulting orange solution wasallowed to warm to rt. After 1 h, the reaction was cooled to 0° C. andSEMC1 (0.27 mL, 1.52 mmol) was added dropwise. The resulting peachsolution was allowed to warm to rt. After 1 h and 45 min, the cloudyyellow mixture was cooled to 0° C. and quenched with water (20 mL). Thereaction was extracted with EtOAc (3×20 mL). The combined organic layerswere washed with water (3×6 mL), dried over Na₂SO₄, filtered andconcentrated. Purification by normal phase chromatography gave 462.5 mg(64%) of 1C as a pale yellow oil. MS (ESI) m/z: 514.3(M+H)⁺.

1D.[(E)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester, 1 TFA salt; and 1E.[(Z)—(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-8-oxa-16,18-diaza-tricyclo[13.2.1.02,7]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester, 1 TFA salt: (Flask 1): To a flame-dried RBF wasadded Grubbs (II) (681 mg, 0.802 mmol). The flask was degassed withargon for several minutes and then degassed DCM (10 mL) was added togive a clear, burgundy solution. (Flask 2): To a separate flame-driedRBF was added 1C (412 mg, 0.802 mmol), pTsOH monohydrate (168 mg, 0.882mmol) and DCM (779 mL). The flask was equipped with a reflux condenserand the solution was degassed with argon for 30 min. Next, the reactionwas warmed to 40° C. After 1 h, the solution of Grubbs (II) was addeddropwise. After 1 h, the reaction was cooled to rt and washed withNaHCO₃, brine, dried over MgSO₄, filtered and concentrated. Purificationby normal phase chromatography gave a pale, brown oil. Furtherpurification by reverse phase chromatography gave 78.6 mg (20%) of 1D(E-alkene) as a pale brown oil and 33.2 mg (9%) of 1E (Z-alkene) as apale, brown oil. For 1D: MS (ESI) m/z: 486.5 (M+H)⁺. For 1E: MS (ESI)m/z: 486.5 (M+H)⁺.

1F.(E)-(S)-(8-Pxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)amine,2 TFA: A yellow solution of 1D (59.2 mg, 0.122 mmol) in 5M HCl (2.50 mL,82 mmol) and EtOH (2.44 mL) was heated to 50° C. After stirringovernight, the reaction was concentrated to remove EtOH and theremaining aqueous layer was adjusted to pH>10 with sat. K₂CO₃. Thereaction was extracted with EtOAc (3×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give a brown residue.Purification by reverse phase chromatography gave 0.0246 g (42%) of 1Fas a clear, colorless oil. MS (ESI) m/z: 256.3 (M+H)⁺.

1G. Example 1: To a solution of Intermediate 1 (33.5 mg, 0.096 mmol) and1F (24.6 mg, 0.096 mmol) in DMF (0.321 mL) was added Hunig's Base (0.084mL, 0.482 mmol). After 45 min, water was added to give a suspension. Thesolid was collected by filtration. Purification by reverse phasechromatography gave after concentration and lyophilization 0.0195 g(33%) of Example 1 as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm2.40-2.71 (m, 3H), 2.76-2.88 (m, 1H), 3.68-3.84 (m, 1H), 4.21-4.42 (m,1H), 5.13-5.28 (m, 2H), 5.77-5.91 (m, 1H), 6.81 (d, J=15.9 Hz, 1H),7.14-7.23 (m, 2H), 7.29 (dd, J=8.2, 1.1 Hz, 1H), 7.47 (td, J=7.7, 1.6Hz, 1H), 7.55 (s, 1H), 7.57-7.62 (m, 2H), 7.69 (dd, J=8.8, 2.2 Hz, 1H),8.00 (d, J=2.2 Hz, 1H), 9.54 (s, 1H). MS (ESI) m/z: 488.3(M+H)⁺.Analytical HPLC: RT=5.35 min.

Example 2(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N—(S)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl-acrylamide,1 TFA salt

2A. (S)-2-(2-Bromophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)pent-4-enoate: To a clear, colorlesssolution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (3.33 g,15.47 mmol) in DMF (38.7 mL) was added potassium hydrogen carbonate(1.859 g, 18.57 mmol). The reaction was stirred for 20 min at rt andthen it was cooled to 0° C. Next a solution of2-bromo-1-(2-bromophenyl)ethanone (4.3 g, 15.47 mmol) in DMF (38.7 mL)was added dropwise and the reaction was allowed to warm to rt. After 3h, the reaction was cooled to 0° C., poured into ice-cold water, andthen extracted with EtOAc (3×). The combined organic layers were washedwith water (1×), brine (1×), dried over sodium sulfate, filtered andconcentrated to give 2A (6.37 g) as a yellow oil which solidified onstorage in the freezer. MS (ESI) m/z: 410.2 (M−H)⁻, 412.2 (M+2-H)⁻. Thematerial was used in the next step without further purification.

2B. (S)-tert-Butyl1-(5-(2-bromophenyl)-1H-imidazol-2-yl)but-3-enylcarbamate: To the clear,yellow solution of 2A (6.37 g, 15.45 mmol) in xylene (155 mL) was addedammonium acetate (11.91 g, 155 mmol). The reaction mixture was heated toreflux with a Dean-Stark trap to remove water azeotropically. After 4 h,the reaction was cooled to rt, diluted with EtOAc (500 mL) and thenwashed with sat. sodium bicarbonate, brine, dried over sodium sulfate,filtered, and concentrated to give a brown residue. Purification bynormal phase chromatography afforded 2B (2.768 g, 45.7%) as a yellowsolid. MS (ESI) m/z: 392.3 (M+H)⁺, 394.3 (M+2+H)⁺.

2C. (S)-tert-Butyl1-(4-(2-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-enylcarbamate:To a cooled (0° C.), suspension of NaH (60% dispersion in mineral oil,0.299 g, 7.48 mmol) in THF (10.0 mL) was added dropwise a solution of 2B(2.668 g, 6.80 mmol) in THF (15.0 mL). Gas evolution was observed. Theflask containing 2B was rinsed with THF (2.2 mL) and then this solutionwas added to the reaction mixture. The resulting clear orange solutionwas stirred at 0° C. for 30 min, then SEM-C1 (1.206 mL, 6.80 mmol) wasadded dropwise. The resulting orange solution was maintained at 0° C.After 3 h, the reaction was quenched with sat. ammonium chloride anddiluted with EtOAc (200 mL) and water. The layers were separated and theaqueous layer was extracted with EtOAc (1×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to give clear orange oil. Purification by normal phasechromatography gave 2C (2.76 g, 78%) as a yellow oil. MS (ESI) m/z:522.5 (M+H)⁺, 524.5 (M+2+H)⁺.

2D. (S)-tert-Butyl1-(4-(2-(pent-4-enyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-3-enylcarbamate:To a flame-dried, thick-walled vial was placed 2C (1.085 g, 2.076 mmol),pent-4-enylboronic acid (0.757 g, 6.64 mmol), silver oxide (1.203 g,5.19 mmol), potassium carbonate (1.722 g, 12.46 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (0.170 g, 0.208 mmol). The vial was purgedwith argon for several minutes and then degassed THF (8.3 mL) was added.The vial was sealed with a teflon-coated screw cap and the blacksuspension was warmed to 80° C. After 16 h the reaction was cooled tort. The reaction mixture was diluted with EtOAc, washed with water, sat.sodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated to give an orange-brown residue. Purification by normalphase chromatography yielded a clear, colorless oil which was a mixtureof 2D and starting material. The material was purified further byreverse phase chromatography. The pure fractions were neutralized withsat. sodium bicarbonate and then concentrated to remove the organicsolvent. The remaining residue was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated to afford 2D (0.21 g, 20%) as aclear, colorless oil. MS (ESI) m/z: 512.6 (M+H)⁺.

2E.[(E)-(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester and 2F.[(Z)—(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl]-carbamicacid tert-butyl ester: (Flask 1): To a flame-dried flask was addedGrubbs (II) (0.139 g, 0.164 mmol). The flask was degassed with argon forseveral minutes and then degassed DCM (2 mL) was added to give a clear,burgundy solution. (Flask 2): To a separate flame-dried RBF was added 2D(0.21 g, 0.410 mmol), p-toluenesulfonic acid monohydrate (0.086 g, 0.451mmol) and DCM (420 mL). The flask was equipped with a reflux condenserand the solution was degassed with argon for 30 min. The reaction washeated to 40° C. After 1 h, the solution of Grubbs (II) was addeddropwise. After 1 h, the reaction was cooled to rt, washed with sat.sodium bicarbonate, brine, dried over MgSO₄, filtered and concentratedto give a brown foam. Purification by reverse phase chromatography gave,after neutralization and extractive workup as described in 2D, 2E (0.09g, 45.3%, E-alkene) as a yellow solid and 2F (0.035 g, 17.6%, Z-alkene)as a yellow solid. For 2E: MS (ESI) m/z: 484.6 (M+H)⁺. For 2F: MS (ESI)m/z: 484.6 (M+H)⁺.

2G.[(S)-16-(2-Trimethylsilanyl-ethoxymethyl)-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To the solution of 2E and 2F (mixture of E/Zisomers) (0.049 g, 0.101 mmol) in MeOH (3 mL) was added 10% palladium oncarbon (10.78 mg, 10.13 mmol). The reaction mixture was stirred underH₂-balloon. After 2 h, the reaction was filtered through a 0.45 μm glassmicrofiber filter (GMF) and the Pd/C was rinsed with MeOH. The filtratewas concentrated to give 2G (0.046 g, 93%) as a clear, colorlessresidue. MS (ESI) m/z: 486.7 (M+H)⁺. The material was used in the nextstep without further purification.

2H. Example 2 was prepared by following the procedures described in step1F, by replacing 1D with 2G; followed by step 1G. ¹H NMR (500 MHz, 50°C., CD₃OD) δ ppm 9.47 (s, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.67 (dd, J=8.8,2.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.43-7.49 (m, 3H), 7.32-7.39 (m,2H), 7.18 (d, J=16.0 Hz, 1H), 6.76 (dd, J=15.7, 3.6 Hz, 1H), 4.99-5.04(m, 1H), 2.52-2.60 (m, 1H), 2.40-2.48 (m, 1H), 2.18-2.26 (m, 1H),1.84-1.90 (m, 1H), 1.31-1.58 (m, 4H), 1.21-1.29 (m, 2H), 0.87-1.01 (m,1H), 0.40-0.54 (m, 1H). MS (ESI) m/z: 488.0 (M+H)⁺. Analytical HPLC:R_(T)=5.78 min.

Example 3 2 TFA Salt

3A.(E)-(S)-(16,18-Diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)amine,2 TFA salt: This compound was prepared following the proceduresdescribed in 1F, by replacing 1D with 2E. MS (ESI) m/z: 254.5 (M+H)⁺.

3B.{4-[(E)-(S)-(16,18-Diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-14-yl)carbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester: To a solution of 3A (0.014 g, 0.029 mmol) in DMF(0.5 mL) was added(1r,40-4-((tert-butoxycarbonylamino)methyl)cyclohexanecarboxylic acid(8.23 mg, 0.032 mmol), EDC (0.011 g, 0.058 mmol), HOBt (8.91 mg, 0.058mmol) and Hunig's base (0.015 g, 0.116 mmol). The reaction was stirredat rt for 16 h and then quenched with water to give a suspension. Thesolid was collected by filtration and then the solid was rinsed withwater, air-dried, and then dried in a vacuum oven (50° C.) for 2 h toafford 3B (0.010 g, 69.8%) as white solid. MS (ESI) m/z: 293.7 (M+H)⁺.The material was used in the next step without further purification.

3C. Example 3: To a solution of 3B (0.01 g, 0.020 mmol) in DCM (0.3 mL)was added TFA (0.3 mL, 3.89 mmol). The reaction was stirred at rt for 1h, and then concentrated. Purification by reverse phase chromatographyafforded Example 3 (0.0095 g, 73.7%) as a white solid. ¹H NMR (500 MHz,50° C., CD₃OD) δ ppm 7.40-7.45 (m, 2H), 7.38 (s, 1H), 7.29-7.37 (m, 2H),5.48-5.56 (m, 1H), 5.07-5.15 (m, 1H), 5.01 (dd, J=10.4, 4.9 Hz, 1H),2.75-2.84 (m, 3H), 2.58-2.66 (m, 1H), 2.43-2.51 (m, 2H), 2.35-2.45 (m,1H), 1.82-2.03 (m, 6H), 1.44-1.69 (m, 4H), 1.20-1.30 (m, 1H), 1.06-1.18(m, 2H). MS (ESI) m/z: 393.6 (M+H)⁺. Analytical HPLC: RT=3.70 min.

Example 8{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

Example 8 was prepared following the procedures described in step 2A, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 7;followed by steps 2B-2C; 2E/2F-2G; 1F, by replacing ethanol withmethanol and by running the reaction at 75° C.; and 1G. ¹H NMR (500 MHz,CD₃OD) δ ppm 9.52 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.2, 2.2Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.48-7.52 (m, 2H), 7.46 (d, J=8.2 Hz,1H), 7.21 (dd, J=8.8, 2.2 Hz, 1H), 7.16 (d, J=15.9 Hz, 1H), 6.78 (d,J=15.9 Hz, 1H), 5.14 (dd, J=10.4, 6.0 Hz, 1H), 3.82-3.88 (m, 1H), 3.75(s, 3H), 3.67-3.72 (m, 1H), 2.19-2.28 (m, 1H), 1.84-1.99 (m, 2H),1.46-1.62 (m, 2H), 1.35-1.45 (m, 1H), 1.11-1.21 (m, 1H), 0.88-0.99 (m,1H). MS (ESI) m/z: 562.9 (M+H)⁺. Analytical HPLC: RT=5.65 min.

Example 9{(S)-17-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-8-oxa-16,18-diaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

To a solution of Example 8 (0.013 g, 0.019 mmol) in acetonitrile (0.5mL)/chloroform (0.500 mL) was added Hunig's base (6.69 mL, 0.038 mmol).The reaction was stirred at rt for 10 min, then NCS (3.08 mg, 0.023mmol) was added. The vial was sealed with a teflon-coated screw cap andthe reaction was warmed to 65° C. After 4 h, additional NCS (3.08 mg,0.023 mmol) was added. After another 2 h, the reaction was cooled to rtand then concentrated. Purification by reverse phase chromatographyafforded 0.0050 g (35.5%) of Example 9 as a yellow solid. ¹H NMR (500MHz, CD₃OD) δ ppm 9.52 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.67 (dd, J=8.5,2.5 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.47-7.51 (m, 2H), 7.20 (dd, J=8.8,2.2 Hz, 1H), 7.15 (d, J=15.4 Hz, 1H), 6.77 (d, J=15.4 Hz, 1H), 5.05 (dd,J=10.4, 6.0 Hz, 1H), 3.80-3.85 (m, 1H), 3.75 (s, 3H), 3.64-3.70 (m, 1H),2.13-2.22 (m, 1H), 1.81-1.92 (m, 2H), 1.49-1.61 (m, 2H), 1.30-1.41 (m,1H), 1.10-1.20 (m, 1H), 0.89-1.01 (m, 1H). MS (ESI) m/z: 597.0 (M+H)⁺.Analytical HPLC: RT=8.09 min.

Example 10{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

10A.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-3H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 2A, by replacing 2-bromo-1-(2-bromophenyl)ethanonewith Intermediate 8; followed by step 2B. MS (ESI) m/z: 467.1 (M+2+H)⁺.

10B.{3-Bromo-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: (The following is an alternative procedure toprocedure 2C). To a cooled (0° C.) solution of 10A (15 g, 32.2 mmol) inTHF (77 mL) was added N,N-dicyclohexylmethylamine (7.52 mL, 35.5 mmol)followed by the dropwise addition of SEM-C1 (6.29 mL, 35.5 mmol). Thereaction was stirred at 0° C. for 2 h and then it was allowed to warmslowly to rt. After 18 h, the yellow suspension was diluted with EtOAc,washed with sat. sodium bicarbonate, brine, dried over MgSO₄, filteredand concentrated. Purification by normal phase chromatography gave 12.24g (63.8%) of 10B as an off-white solid. MS (ESI) m/z: 595.1 (M+H)⁺ and597.2 (M+2+H)⁺.

10C.{3-Amino-4-[2-((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: A thick-walled vial containing 10B (2 g, 3.36 mmol),copper(I) iodide (0.128 g, 0.672 mmol), L-proline (0.155 g, 1.343 mmol)and potassium carbonate (1.392 g, 10.07 mmol) in DMSO (6.72 mL) wasvacuumed and back-filled with argon three times. Then 28% aq. ammoniumhydroxide (0.607 mL, 4.37 mmol) was added. The vial was sealed with ateflon-coated screw cap and the reaction was warmed to 85° C. After 20h, the reaction was cooled to rt, diluted with EtOAc, washed with water,brine, dried over sodium sulfate, filtered and concentrated.Purification by normal phase chromatography afforded 1.05 g (58.8%) of10C as a yellow solid. MS (ESI) m/z: 532.5 (M+H)⁺.

10C (Alternative route). Compound 10B (1.0 g, 1.679 mmol), copper(I)iodide (0.032 g, 0.168 mmol), L-proline (0.058 g, 0.504 mmol) and sodiumazide (0.131 g, 2.015 mmol) were added to a 35 mL pressure tube. Next,EtOH (2.52 mL), water (0.839 mL), and 1N NaOH (0.504 mL, 0.504 mmol)were added. The reaction vessel was vacuumed and back-filled with argonthree times. The pressure tube was sealed with a teflon screw cap,containing a viton O-ring, and then the reaction was warmed to 95° C.After 20 h, the reaction was cooled to rt, and additional sodium azide(0.131 g, 2.015 mmol), L-proline (0.058 g, 0.504 mmol), copper(I) iodide(0.032 g, 0.168 mmol), NaOH (0.504 mL, 0.504 mmol) and EtOH (2.52 mL)were added. The vessel was sealed and the reaction was warmed to 95° C.After another 24 h, the reaction was cooled to rt, diluted with EtOAc,washed with water, brine, dried over sodium sulfate, filtered andconcentrated. Purification by normal phase chromatography gave 0.475 g(53.2%) of 10C as an orange solid. MS (ESI) m/z: 532.4 (M+H)⁺.

10D.{3-But-3-enoylamino-4-[2((S)-1-tert-butoxycarbonylamino-but-3-enyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a cooled (−10° C.) solution of Hunig's base (0.300mL, 1.715 mmol), but-3-enoic acid (0.049 g, 0.572 mmol) and 10C (0.304g, 0.572 mmol) in ethyl acetate (16.34 mL) was added 1-propanephosphonicacid cyclic anhydride (T3P) (50% in EtOAc, 0.674 mL, 1.143 mmol). After5 min, the reaction was allowed to warm to rt. After 1 h at rt, thereaction was concentrated. Purification by normal phase chromatographygave 0.30 g (87%) of 10D as a yellow solid. MS (ESI) m/z: 600.3 (M+H)⁺.

10E.[(E)-(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl]-carbamicacid methyl ester; and 10F.[(Z)—(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,11,15(18)-hexaen-5-yl]-carbamicacid methyl ester: Compound 10E, the E-alkene, and compound 10F, theZ-alkene, were prepared following the procedure described in 2E/2F, byreplacing 2D with 10D. MS (ESI) m/z: 572.2 (M+H)⁺.

10G.[(S)-14-tert-Butoxycarbonylamino-9-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl]-carbamicacid methyl ester: To a suspension of 10E (0.25 g, 0.437 mmol) in MeOH(10 mL)/EtOAc (5 mL) was added 10% palladium on carbon (0.047 g, 0.044mmol). Hydrogen was bubbled through the reaction mixture for 5 min andthen the reaction was stirred vigorously under a hydrogen atmosphere(balloon). After 24 h, the reaction was filtered through a 0.45 nm GMF,rinsing with MeOH, DCM and EtOAc. The filtrate was concentrated andpurification by reverse phase chromatography afforded 0.220 g (88%) of10G, as an off-white solid. MS (ESI) m/z: 574.4 (M+H)⁺.

10H.((S)-14-Amino-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl)-carbamicacid methyl ester, 2HCl salt: A mixture of 10G (0.099 g, 0.173 mmol) and4M HCl in dioxane (2 mL, 8.00 mmol) in a sealed tube was heated at 50°C. After 2 h, the yellow suspension was cooled to rt and thenconcentrated. The residue was suspended in MeOH (0.2 mL) and Et₂O. Thesolid was collected by filtration. The solid was rinsed with Et₂O,air-dried (very hygroscopic) to afford 0.053 g (73.8%) of 10H as ayellow solid. MS (ESI) m/z: 344.2 (M+H)⁺.

10I. Example 10 was prepared following the procedure described in 1G, byreplacing 1F with 10H. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (s, 1H), 7.97(d, J=2.2 Hz, 1H), 7.67 (dd, J=8.2, 2.2 Hz, 1H), 7.55-7.60 (m, 2H), 7.50(d, J=8.2 Hz, 1H), 7.44 (s, 1H), 7.42 (dd, J=8.3, 2.2 Hz, 1H), 7.13 (d,J=15.4 Hz, 1H), 6.76 (d, J=15.9 Hz, 1H), 5.13 (dd, J=10.2, 6.3 Hz, 1H),3.75 (s, 3H), 2.42-2.52 (m, 1H), 2.17-2.29 (m, 1H), 2.05-2.15 (m, 1H),1.96 (m, 1H), 1.51-1.71 (m, 2H), 1.36-1.49 (m, 1H), 0.92-1.07 (m, 1H).MS (ESI) m/z: 576.3 (M+H)⁺. Analytical HPLC: RT=4.60 min.

Example 15(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N—((S)-9-oxo-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl)-acrylamide,1 TFA salt

15A.{(S)-1-[4-(2-Nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: This compound was prepared following theprocedures described in step 2A, by replacing2-bromo-1-(2-bromophenyl)ethanone with2-bromo-1-(2-nitrophenyl)ethanone; followed by steps 2B, by replacingxylene with toluene; and 2C. MS (ESI) m/z: 489.4(M+H)⁺.

15B.{(S)-1-[4-(2-Amino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-but-3-enyl}-carbamicacid tert-butyl ester: To a yellow solution of 15A (1.0441 g, 2.137mmol) in MeOH (14.15 mL) was added zinc dust (1.397 g, 21.37 mmol) andammonium chloride (1.143 g, 21.37 mmol). The gray suspension was stirredvigorously at rt. After 1 h, the flask was equipped with a refluxcondenser and the reaction was warmed to 60° C. After 1 h, the reactionwas cooled to rt and allowed to stir overnight. The reaction wasfiltered through a 0.45 μm GMF, eluting with methanol. The filtrate wasconcentrated to give a yellow solid. The solid was partitioned betweenEtOAc and 0.5M HCl (aq). The layers were separated and the aqueous layerwas extracted with EtOAc (1×). The combined organic layers were washedwith sat. NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated togive an orange oil. Purification by normal phase chromatography gave0.818 g (83%) of 15B as a yellow foam. MS (ESI) m/z: 459.4(M+H)⁺.

15C.(S)-14-Amino-8,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-9-one,2HCl: This compound was prepared following the procedures in step 10D,by replacing 10C with 15B; followed by steps 2E/2F; 2G, by replacing thehydrogen balloon with hydrogen (50-55 psi); and 10H. MS (ESI) m/z:489.4(M+H)⁺.

15D. Example 15: A suspension of Intermediate 2 (0.074 g, 0.296 mmol),15C (0.113 g, 0.329 mmol), EDC (0.095 g, 0.494 mmol), and HOBT (0.076 g,0.494 mmol) in DMF (1.65 mL) and Hunig's Base (0.172 mL, 0.988 mmol) wasstirred at rt overnight. Water was added to the brown solution to give asuspension. The mixture was extracted with EtOAc (2×). The organiclayers were combined and washed with sat. NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. Purification by reverse phasechromatography gave 0.0964 g (47%) of Example 15 as a white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 0.96-1.13 (m, 1H), 1.37-1.50 (m, 1H),1.51-1.72 (m, 2H), 1.90-2.01 (m, 1H), 2.05-2.15 (m, 1H), 2.18-2.28 (m,1H), 2.44-2.50 (m, 1H), 5.13 (dd, J=10.2, 6.3 Hz, 1H), 6.75 (d, J=15.7Hz, 1H), 7.14 (d, J=15.7 Hz, 1H), 7.31 (dd, J=7.8, 0.7 Hz, 1H), 7.44(td, J=7.6, 1.1 Hz, 1H), 7.49 (s, 1H), 7.53 (td, J=7.7, 1.4 Hz, 1H),7.58 (d, J=8.5 Hz, 1H), 7.61 (dd, J=7.7, 1.4 Hz, 1H), 7.67 (dd, J=8.5,2.5 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 9.50 (s, 1H). MS (ESI) m/z:503.3(M+H)⁺. Analytical HPLC: RT=4.72 min.

Example 23{(S)-14-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-11-methyl-12-oxo-11,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

23A.(S)-3-[4-(2-Bromo-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: This compound was prepared following the proceduresdescribed in 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-2-tert-butoxycarbonylamino-succinic acid 4-benzyl ester, byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8 and byreplacing potassium hydrogen carbonate with potassium carbonate;followed by steps 2B, by replacing xylene with toluene; and 10B. MS(ESI) m/z: 703.3, 705.3 (M+H)⁺.

23B. Methyl-prop-2-ynyl-carbamic acid benzyl ester: To a solution ofN-methylprop-2-yn-1-amine (3.50 g, 50.6 mmol) in DCM (50 mL) were addedTEA (8.47 mL, 60.8 mmol) and Cbz-Cl (7.95 mL, 55.7 mmol) dropwise at 0°C. The reaction was stirred under argon at 0° C. for 1 h. The reactionmixture was diluted with CH₂Cl₂, washed with 1M HCl, saturated NaHCO₃and brine. The organic phase was dried over MgSO₄, filtered andconcentrated to give 23B (10.02 g, 97% yield) as a clear oil. MS (ESI)m/z: 204.1 (M+H)⁺.

23C.(S)-3-[4-{2-[3-(Benzyloxycarbonyl-methyl-amino)-prop-1-ynyl]-4-methoxycarbonylamino-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: To a solution of 23A (200 mg, 0.284 mmol) in DMF (5mL) was added 23B (69.3 mg, 0.341 mmol), CuI (10.83 mg, 0.057 mmol), TEA(0.119 mL, 0.853 mmol) and Pd(Ph₃P)₄ (32.8 mg, 0.028 mmol). The reactionwas purged with argon for 3 min and then stirred under argon at 90° C.for 6 h. The reaction was cooled to rt and diluted with EtOAc. Theorganic layer was washed with saturated NaHCO₃ and brine, dried overMgSO₄, filtered and concentrated. The crude product was purified bynormal phase chromatography to give 23C (205 mg, 87% yield) as a solid.LC-MS (ESI) m/z: 826.5 (M+H)⁺.

23D.(S)-3-(tert-Butoxycarbonylamino)-3-(4-(4-(methoxycarbonylamino)-2-(3-(methylamino)propyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)propanoicacid, TFA salt: This compound was prepared following the proceduredescribed in 2G, by replacing 2E with 23C. MS (ESI) m/z: 606.4 (M+H)⁺.

23E.[(S)-5-Methoxycarbonylamino-11-methyl-12-oxo-16-(2-trimethylsilanyl-ethoxymethyl)-11,16,18-triaza-tricyclo[13.2.1.0^(2,7)]octadeca-1(17),2,4,6,15(18)-pentaen-14-yl]-carbamicacid tert-butyl ester: To a solution of DMAP (23.19 mg, 0.190 mmol),DIEA (0.166 mL, 0.949 mmol) and BOP (168 mg, 0.380 mmol) in DCM (20 mL)was added a solution of 23D (115 mg, 0.190 mmol) in DMF (2 mL) at rtthrough a syringe pump over 1.5 h. Upon addition, the reaction wasstirred for another 30 min and the solvent was removed. The crudeproduct was purified by reverse phase chromatography to give 23E (44 mg,39.4% yield) as a solid. MS (ESI) m/z: 588.4 (M+H)⁺.

23F. Example 23 was prepared following the procedures described in step1F, by replacing 1D with 23E and by replacing ethanol with methanol;followed by step 1G. ¹H NMR (400 MHz, CD₃OD, rotamers) δ ppm 9.52 (twosinglets, 1H), 9.36 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.68 (ddd, J=8.6,6.3, 2.3 Hz, 1H), 7.59 (dd, J=8.5, 5.5 Hz, 1H), 7.49-7.43 (m, 1H),7.41-7.33 (m, 3H), 7.19 (two doublets, J=16.0 Hz, 1H), 6.81 (twodoublets, J=15.6 Hz, 1H), 5.49 (dd, J=8.7, 4.8 Hz, 1H), 4.12 (ddd,J=7.3, 6.0, 3.7 Hz, 1H), 3.75 (two singlets, 3H), 3.55-3.43 (m, J=9.2,7.6, 5.9 Hz, 1H), 3.00 (two singlets, 3H), 2.81 (dd, J=13.9, 4.8 Hz,1H), 2.69-2.57 (m, 2H), 2.48-2.28 (m, 1H), 1.91-1.76 (m, 1H), 1.64-1.44(m, 1H). LC-MS (ESI) m/z: 590.2 (M+H)⁺. Analytical HPLC: RT=5.328 min.

Example 52{(R)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-13-oxa-8,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

52A. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid methylester: This compound was prepared following a procedure described inOrganic Letters, 10(17):3883 (2008). To a solution ofN-(tert-butoxycarbonyl)-L-serine methyl ester (0.781 mL, 3.85 mmol) inTHF (15 mL) was added allyl methyl carbonate (0.524 mL, 4.61 mmol). Thesolution was purged with N₂, followed by the addition oftetrakis(triphenylphosphine)palladium(0) (444 mg, 0.385 mmol). Thevessel was sealed and heated at 60° C. overnight. The reaction mixturewas diluted with ethyl acetate, washed with sat NaHCO₃, and brine. Theorganic layer was concentrated. Purification by normal phasechromatography provided 52A (550 mg, 55.2% yield) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 5.75-5.94 (m, 1H) 5.32-5.47 (m, 1H) 5.11-5.29(m, 2H) 4.35-4.53 (m, 1H) 3.92-4.03 (m, 2H) 3.80-3.89 (m, 1H) 3.76 (m,3H) 3.61-3.70 (m, 1H) 1.46 (m, 9H).

52B. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid: Asolution of 52A (1000 mg, 3.86 mmol) and lithium hydroxide (486 mg,11.57 mmol) in THF, water and MeOH was stirred at rt for 4 h. Thesolution was acidified using 5M HCl in water (pH −3). The mixture wasextracted with EtOAc. The combined organic layers were concentrated togive 52B (0.96 g, 100% yield) as a yellow oil. MS (ESI) m/z: 146.0(M+H-boc)⁺.

52C. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(2-bromo-4-nitro-phenyl)-2-oxo-ethyl ester: To a solution of 52B (0.95g, 3.87 mmol) and Intermediate 10 (1.376 g, 4.26 mmol) in DMF (20 mL)was added potassium bicarbonate (0.465 g, 4.65 mmol). After 1.5 h at rt,the reaction was diluted with EtOAc, washed with water, saturated sodiumbicarbonate solution, then brine, dried over magnesium sulfate,filtered, and concentrated to give 52C (1.82 g, 96% yield) as a thickorange oil. MS (ESI) m/z: 389.0(M+H-boc)⁺.

52D. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(4-amino-2-bromo-phenyl)-2-oxo-ethyl ester: To a mixture of 52C (1700mg, 3.49 mmol) and iron (3896 mg, 69.8 mmol) in ethanol (15 mL) andwater (15.00 mL) was added 12M conc. HCl (0.204 mL, 2.442 mmol). Thesuspension was heated at 50° for 2 hr. The dark suspension was filtered,washed with methanol and concentrated to give 52D (1.7 g, 100%). MS(ESI) m/z: 359.0(M+H-boc)⁺.

52E. (S)-3-Allyloxy-2-tert-butoxycarbonylamino-propionic acid2-(2-bromo-4-methoxycarbonylamino-phenyl)-2-oxo-ethyl ester: To a cooled(ice bath) solution 52D (1670 mg, 3.65 mmol) and pyridine (0.325 mL,4.02 mmol) in dichloromethane (50 mL) was added methyl chloroformate(0.297 mL, 3.83 mmol). The reaction mixture was stirred for 10 min,washed with brine, dried (MgSO₄) and concentrated to give 52E (1.8 g,96% yield) as a yellow foam. MS (ESI) m/z: 417.1(M+H-boc)⁺.

52F.{4-[2-((R)-2-Allyloxy-1-tert-butoxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-3-amino-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 1B, by replacing 1A with 52E; followed by steps 10B;and 10C (alternative). MS (ESI) m/z: 562.3(M+H)⁺.

52G.{3-Acryloylamino-4-[2-((R)-2-allyloxy-1-tert-butoxycarbonylamino-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: A solution of 52F (50 mg, 0.089 mmol), and DIEA (50μL, 0.286 mmol) in THF (2 mL) was cooled in ice bath. Acryloyl chloride(10 μL, 0.123 mmol) was added into the solution in a portion. Then, theice bath was removed and reaction mixture was stirred for 1 hr at rt. Tothe reaction mixture was added sat. NaHCO₃ and the mixture was extractedwith EtOAc. The combined organic layer were washed with brine andconcentrated to provide an oily residue, which has gel like materialinsoluble in CH₂Cl₂. The soluble portion of the residue was purified bynormal phase chromatography to give 52G (43 mg, 78% yield). MS (ESI)m/z: 616.4 (M+H)⁺.

52H. Example 52 was prepared following the procedures described in step2E/2F, by replacing 2D with 52G; followed by steps 2G; 10H; and 1G. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.94 (s, 1H) 7.79 (s, 1H) 7.50-7.62 (m, 1H)7.42 (t, J=7.91 Hz, 2H) 7.10 (br. s., 1H) 6.60 (d, J=15.31 Hz, 1H) 5.22(br. s., 1H) 4.04-4.18 (m, 1H) 3.92-4.02 (m, 1H) 3.78 (s, 4H) 3.60 (d,J=6.27 Hz, 2H) 3.28-3.49 (m, 1H) 2.81 (t, J=7.28 Hz, 1H) 2.34 (s, 1H)2.05 (d, J=5.02 Hz, 2H) 1.63 (br. s., 1H) 0.88 (t, J=6.90 Hz, 2H). MS(ESI) m/z: 592.3(M+H)⁺. Analytical HPLC: RT=5.16 min.

Example 72{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-methyl-13-oxo-12,17,19-triaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 1 TFA salt

72A.(S)-3-[4-(2-Allyl-4-methoxycarbonylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-3-tert-butoxycarbonylamino-propionicacid benzyl ester: 23A (0.30 g, 0.426 mmol), allyltributylstannane(0.282 g, 0.853 mmol), CsF (0.162 g, 1.065 mmol), Pd₂ dba₃ (0.020 g,0.021 mmol), and tri-(tert-butyl)phosphine (0.173 g, 0.085 mmol) wereadded together with dioxane (10 mL). The mixture was heated to 90° C.under argon. After 2.5 h, an additional two equivalents ofallyltributylstannane and CsF, and a catalytic amount of Pd₂ dba₃ andtri-(tert-butyl)phosphine were added. The mixture was stirred at 90° C.under argon for 3 h. The solvent was removed and the residue waspartitioned between EtOAc and water. The EtOAc solution was washed withbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by normal phase chromatography to give 72A (0.26 g, 92% yield).MS (ESI) m/z: 665.3 (M+H)⁺.

72B.(S)-3-(4-(2-Allyl-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(tert-butoxycarbonylamino)propanoicacid: 72A (0.26 g, 0.39 mmol) was dissolved in THF (6 mL) and 2N LiOH (2mL) was added. The mixture was stirred at rt under argon for 20 h. Thesolvent was removed and the residue was diluted with water and acidifiedto pH about 5 with 1N HCl. The mixture was extracted with EtOAc. Thecombined EtOAc solution was washed with brine, dried over Na₂SO₄ andconcentrated to give 72B (0.24 g, 100% yield). MS (ESI) m/z: 575.3(M+H)⁺.

72C.{3-Allyl-4-[2-[(S)-2-(allyl-methyl-carbamoyl)-1-tert-butoxycarbonylamino-ethyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a solution of 72B in DMF (4 mL) were added PyBOP(0.26 g, 0.47 mmol), Et₃N (0.22 mL, 1.56 mmol), and methylallylamine(0.71 g, 0.998 mmol). The mixture was stirred at rt under argon for 1.5h. Water was added and the mixture was extracted with EtOAc. Thecombined EtOAc solution was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by normal phasechromatography to give 72C (0.16 g, 64% yield). MS (ESI) m/z: 628.4(M+H)⁺.

72D. Example 72 was prepared following the procedures described in step2E/2F, by replacing 2D with 72C; followed by steps 2G; 1F, by replacingethanol with methanol; and 1G. ¹H NMR (400 MHz, CD₃OD, rotamers) δ ppm9.52 (s, 1H), 9.30 (s, 1H), 8.00 (dd, J=14.56 and 2.26 Hz, 1H),7.64-7.77 (m, 1H), 7.55-7.63 (m, 1H), 7.46 (dd, J=10.42 and 2.13 Hz,1H), 7.36-7.43 (m, 1H), 7.35 (d, J=1.25 Hz, 1H), 7.30 (d, J=8.03 Hz,1H), 7.21 (dd, J=15.69 and 5.14 Hz, 1H), 5.67 (m, 1H), 5.53 (m, 1H),4.46 (m, 1H), 3.75 (two singlets, 3H), 3.47 (m, 1H), 3.28 (m, 2H), 3.25(m, 1H), 2.92 (two singlets, 3H), 2.68 (m, 2H), 2.29 (m, 1H), 1.29 (m,1H). LC-MS (ESI) m/z: 604.3 (M+H)⁺. Analytical HPLC: RT=6.22/6.49 min(two rotational isomers).

Example 79

{(S)-15-[(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-13-oxo-8,12,17,19-tetraaza-tricyclo[14.2.1.0^(2,7)]nonadeca-1(18),2,4,6,16(19)-pentaen-5-yl}-carbamicacid methyl ester, 2 TFA salt

79A. (S)-Benzyl3-(4-(2-(3-(benzyloxycarbonylamino)propylamino)-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(tert-butoxycarbonylamino)propanoate:To a solution of 23A (200 mg, 0.284 mmol) in DMSO were added benzyl3-aminopropylcarbamate, HCl salt (83 mg, 0.341 mmol), L-proline (6.54mg, 0.057 mmol), CuI (5.41 mg, 0.028 mmol) and K₂CO₃ (118 mg, 0.853mmol). The reaction was purged with argon for 3 min. The reaction wasstirred at 80° C. for 16 h. The reaction was cooled to rt and then wasdiluted with EtOAc, washed with H₂O, saturated NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by normal phase chromatography to give 79A (47 mg,20% yield) as a light tan solid. LC-MS (ESI) m/z: 831.4 (M+H)⁺.

79B. Example 79 was prepared following the procedures described in step2G, by replacing 2E with 79A; followed by steps 23E;1F, by replacingethanol with methanol; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (1H,s), 7.99 (1H, d, J=2.26 Hz), 7.83 (1H, s), 7.64-7.71 (2H, m), 7.55-7.62(2H, m), 7.25 (1H, dd, J=8.53, 2.01 Hz), 7.21 (1H, d, J=15.56 Hz), 6.74(1H, d, J=15.56 Hz), 5.60 (1H, dd, J=9.29, 4.27 Hz), 3.77 (3H, s),3.61-3.71 (1H, m), 3.43-3.51 (1H, m), 3.34-3.40 (2H, m), 2.85-2.94 (1H,m), 2.75-2.84 (1H, m), 2.13-2.27 (2H, m). LC-MS (ESI) m/z: 591.2 (M+H)⁺.Analytical HPLC: RT=4.836 min.

Example 86 2 TFA Salt

Example 86 was prepared by following the procedures described in step79A, by replacing benzyl 3-aminopropylcarbamate HCl salt with (S)-benzyl3-(aminomethyl)pyrrolidine-1-carboxylate; followed by steps 2G; 23E;1F,by replacing ethanol with methanol; and 1G. ¹H NMR (conformers, 400 MHz,CD₃OD) δ ppm 9.50-9.60 (1H, m), 7.91-8.15 (1H, m), 7.47-7.86 (4H, m),7.14-7.39 (2H, m), 6.58-7.02 (2H, m), 5.50-5.84 (1H, m), 3.55-4.53 (6H,m), 3.37-3.53 (2H, m), 3.10-3.23 (1H, m), 2.73-2.84 (1H, m), 2.57-2.72(1H, m), 1.64-2.48 (2H, m), 1.21-1.46 (1H, m).

LC-MS (ESI) m/z: 617.2 (M+H)⁺. Analytical HPLC: RT=5.481 min.

Example 89{(E)-17-Chloro-15-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-9-oxo-8,18,19-triaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2,4,6,12,16,18-heptaen-5-yl}-carbamicacid methyl ester

89A. tert-Butyl 1-(3,6-dichloropyridazin-4-yl)but-3-enylcarbamate: To acooled (−78° C.) solution of tert-butyl(3,6-dichloropyridazin-4-yl)methylcarbamate (3.28 g, 11.79 mmol)prepared by following a literature procedure (Cowden, C. J., Org. Lett.,4497-4499 (2003)) in THF (15 mL) was added TMEDA (1.780 mL, 11.79 mmol).Then sec-butyllithium (1.4M in cyclohexane, 21.06 mL, 29.5 mmol) wasadded dropwise at −78° C. The reaction was warmed to −40° C. over 30 minbefore it was cooled to −78° C. Allyl bromide (1.496 mL, 17.69 mmol) wasadded at −78° C. The reaction was stirred under argon at −78° C. for 30min and then was quenched with NH₄Cl solution. The reaction mixture wasdiluted with EtOAc, washed with 1M HCl, saturated NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by normal phase chromatography to give 89A (1.49 g,40% yield) as a solid. LC-MS (ESI) m/z: 318.1 (M+H)⁺.

89B. tert-Butyl1-(6-(2-amino-4-nitrophenyl)-3-chloropyridazin-4-yl)but-3-enylcarbamate:A flask containing 89A (1.49 g, 4.68 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-nitroaniline (1.756 g, 7.02mmol) and Cs₂CO₃ (3.81 g, 11.71 mmol) was purged with argon. To it wereadded dioxane (40 mL), tri-tert-butylphosphine tetrafluoroborate (0.204g, 0.702 mmol) and Pd₂ dba₃ (0.429 g, 0.468 mmol) at rt. The reactionwas stirred under argon at 90° C. for 3 h. The reaction was cooled tort. The solid was filtered off and the solvent was removed to give adark solid. The crude product was purified by normal phasechromatography to give 89B (0.66 g, 34% yield) as a dark brown solid.LC-MS (ESI) m/z: 420.2 (M+H)⁺.

89C. tert-Butyl1-(3-chloro-6-(4-nitro-2-pent-4-enamidophenyl)pyridazin-4-yl)but-3-enylcarbamate:To a solution of 89B (0.66 g, 1.572 mmol) in DCM (20 mL) were added TEA(0.438 mL, 3.14 mmol) and pent-4-enoyl chloride (0.208 mL, 1.886 mmol)at 0° C. The reaction was stirred under argon at 0° C. for 1.5 h. Thereaction mixture was diluted with DCM, washed with 1M HCl, saturatedNaHCO₃ and brine. The organic phase was dried over sodium sulfate,filtered and concentrated to give 89C (0.79 g, 100% yield) as a brownsolid. LC-MS (ESI) m/z: 502.2 (M+H)⁺.

89D. tert-Butyl1-(6-(4-amino-2-pent-4-enamidophenyl)-3-chloropyridazin-4-yl)but-3-enylcarbamate:To a solution of 89C (0.79 g, 1.574 mmol) in methanol (30 mL) were addedzinc powder (0.515 g, 7.87 mmol) and ammonium chloride (0.842 g, 15.74mmol) at 0° C. The reaction was stirred under argon at rt for 4 h. Thesolid was filtered through a pad of CELITE® and the filtrate wasconcentrated to give 89D (0.74 g, 100% yield) as a dark brown solid.LC-MS (ESI) m/z: 472.4 (M+H)⁺.

89E.{4-[5-(1-tert-Butoxycarbonylamino-but-3-enyl)-6-chloro-pyridazin-3-yl]-3-pent-4-enoylamino-phenyl}-carbamicacid methyl ester: To a solution of 89D (0.74 g, 1.568 mmol) in DCM (20mL) and DMF (2 mL)(to make it more soluble) were added pyridine (0.254mL, 3.14 mmol) and methyl chloroformate (0.121 mL, 1.568 mmol) at 0° C.The reaction was stirred under argon at 0° C. for 30 min. Water wasadded to quench the reaction. Most DCM was evaporated. The reactionmixture was diluted with EtOAc, washed with 1M HCl, saturated NaHCO₃ andbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. The crude product was purified by normal phasechromatography to give 89E (501 mg, 60% yield) as a brown solid. LC-MS(ESI) m/z: 530.3⁺.

89F.((E)-17-Chloro-5-methoxycarbonylamino-9-oxo-8,18,19-triaza-tricyclo[14.3.1.0^(2,7)]icosa-1(20),2,4,6,12,16,18-heptaen-15-yl)-carbamicacid tert-butyl ester: To a solution of 89E (350 mg, 0.660 mmol) in DCM(100 mL) was added Grubbs (II) (168 mg, 0.198 mmol) at rt. The solutionwas purged with argon for 3 min and then was stirred under argon atreflux for 1 h. Solvent was removed. The residue was dissolved in EtOAc,which was washed with water and brine. Organic phase was dried overMgSO₄, filtered and concentrated to give a dark solid. The crude productwas purified by normal phase chromatography to give 89F (185 mg, 56%yield) as a brown solid. LC-MS (ESI) m/z: 502.3 (M+H)⁺.

89G. Example 89 was prepared following the procedures described in step3C, by replacing 3B with 89F; followed by step 1G. ¹H NMR (400 MHz,MeOD) δ ppm 9.48 (s, 1H), 8.67 (d, J=4.3 Hz, 1H), 8.14 (s, 1H), 8.00 (s,1H), 7.92 (s, 1H), 7.64 (dd, J=8.5, 1.9 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H),7.45 (dd, J=14.0, 7.6 Hz, 1H), 7.07 (d, J=15.6 Hz, 1H), 6.59 (d, J=15.8Hz, 1H), 5.34-5.11 (m, 2H), 4.58-4.36 (m, 1H), 3.76 (s, 3H), 3.10-2.96(m, 1H), 2.64-2.51 (m, 1H), 2.19 (dd, J=17.9, 11.0 Hz, 3H), 1.30 (t,J=7.3 Hz, 1H). LC-MS (ESI) m/z: 634.3 (M+H)⁺. Analytical HPLC: RT=7.596min.

Example 9416-Chloro-14-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-12-oxo-8-oxa-11,17,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-5-carboxylicacid methyl ester

94A.4-[5-(2-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-ethyl)-6-chloro-pyridazin-3-yl]-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester: To a solution of benzyl3-(tert-butoxycarbonylamino)-3-(3,6-dichloropyridazin-4-yl)propanoate(200 mg, 0.469 mmol) prepared by following a literature procedure(Cowden, C. J., Org. Lett., 4497-4499 (2003)) in dioxane (10 mL) wereadded Intermediate 13 (308 mg, 0.704 mmol), Cs₂CO₃ (382 mg, 1.173 mmol)and tri-tert-butylphosphine tetrafluoroborate (13.61 mg, 0.047 mmol).The solution was purged with argon for 2 min and then Pd₂ dba₃ (21.48mg, 0.023 mmol) was added. The reaction was stirred under argon at 90°C. for 2 h. The solid was filtered-off and the solvent was removed. Thecrude mixture was purified by normal phase chromatography to give 94A(128 mg, 38% yield) as a yellow solid. LC-MS (ESI) m/z: 715.2 (M+H)⁺.

94B.4-[5-(1-tert-Butoxycarbonylamino-2-carboxy-ethyl)-6-chloro-pyridazin-3-yl]-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-benzoicacid methyl ester: To a solution of 94A (128 mg, 0.179 mmol) in MeOH (5mL) and ethyl acetate (5 mL) (more soluble in EtOAc) was added catalyticamount of 10% Pd/C. The reaction was stirred under a hydrogen balloon atrt for 3 h. The catalyst was filtered off and the solvent was removed togive 94B (102 mg, 91% yield) as a yellow solid. LC-MS (ESI) m/z: 625.2(M+H)⁺.

94C.3-(2-Amino-ethoxy)-4-[5-(1-tert-butoxycarbonylamino-2-carboxy-ethyl)-6-chloro-pyridazin-3-yl]-benzoicacid methyl ester, TFA salt: To a solution of 94B (102 mg, 0.163 mmol)in EtOH (5 mL) was added hydrazine (0.1 mL, 3.19 mmol) at rt. Thereaction was stirred under argon at reflux for 30 min. the solvent wasremoved. Purification by reverse phase chromatography gave 94C (25 mg,25.2% yield) as a solid. LC-MS (ESI) m/z: 495.1 (M+H)⁺.

94D.14-tert-Butoxycarbonylamino-16-chloro-12-oxo-8-oxa-11,17,18-triaza-tricyclo[13.3.1.0^(2,7)]nonadeca-1(19),2,4,6,15,17-hexaene-5-carboxylicacid methyl ester: To a solution of BOP reagent (36.3 mg, 0.082 mmol),DIEA (0.036 mL, 0.205 mmol) and DMAP (5.02 mg, 0.041 mmol) in DCM (30mL) was added a solution of 94C (25 mg, 0.041 mmol) in DMF (2.0 mL)through a syringe pump over 2 h at rt. Upon addition, the reaction wasstirred for another 30 min and the solvent was removed. The crudeproduct was purified by reverse phase chromatography to give 94D (3.0mg, 15.32% yield) as a tan solid. LC-MS (ESI) m/z: 477.1 (M+H)⁺.

94E. Example 94 was prepared by following the procedures described instep 3C, by replacing 3B with 94D; followed by step 1G. ¹H NMR (400 MHz,DMF-d₇) δ ppm 9.84 (1H, s), 8.80 (1H, d, J=8.03 Hz), 8.33 (1H, s),8.19-8.28 (1H, m), 8.11 (1H, s), 7.83 (1H, d, J=8.28 Hz), 7.73-7.80 (4H,m), 7.00-7.09 (1H, m), 6.90-6.99 (1H, m), 5.47-5.63 (1H, m), 4.24 (2H,dd, J=5.65, 1.88 Hz), 3.94 (3H, s), 3.61 (2H, t, J=5.90 Hz), 3.03-3.14(2H, m). LC-MS (ESI) m/z: 609.2 (M+H)⁺. Analytical HPLC: RT=7.620 min.

Example 97 1 TFA Salt

97A. (S)-Methyl3-(2-(4-(2-bromo-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)benzoate:This compound was prepared following the procedures described in 2A, byreplacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-2-(tert-butoxycarbonylamino)-3-(3-(methoxycarbonyl)phenyl)propanoicacid and by replacing 2-bromo-1-(2-bromophenyl)ethanone withIntermediate 8; and 2B. MS (ESI) m/z: 573.0 (M+H)⁺.

97B. (S)-Methyl3-(2-(tert-butoxycarbonylamino)-2-(4-(2-cyano-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)ethyl)benzoate:To a 20 mL microwave vial was added 97A (500 mg, 0.872 mmol),dicyanozinc (205 mg, 1.744 mmol), and DMF (7 mL). The mixture(suspension) was degassed for 5 min, andtetrakis(triphenylphosphine)palladium(0) (101 mg, 0.087 mmol) was added.The reaction mixture was heated in a microwave oven at 140° C. for 7min. The reaction was diluted with EtOAc (50 mL) and then washed with 2Mof ammonium hydroxide, water, and brine. It was dried over Na₂SO₄, andconcentrated. The residue was purified by normal phase chromatography togive a pale yellow solid (297 mg, 65.6% yield). MS (ESI) m/z: 520.0(M+H)⁺.

97C.(S)-3-(2-(tert-Butoxycarbonylamino)-2-(4-(2-cyano-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)ethyl)benzoicacid: A solution of lithium hydroxide (21.76 mg, 0.908 mmol) in 1 mL ofwater was added to a solution of 97B (118 mg, 0.227 mmol) in THF (2.5mL) at rt. The colorless solution changed to light cloudy solution uponthe base addition. After 2 h, more LiOH (21.76 mg, 0.908 mmol in 1 mL ofH₂O) was added. The mixture was stirred for another 5 h. The THF wasremoved and the residue was diluted with EtOAc (20 mL). 1N HCl (1.476ml, 1.476 mmol) was added to the mixture with vigorous stirring. Theorganic layers were separated and the aqueous layer was extracted withEtOAc. The combined organic extracts were washed with brine, driedNa₂SO₄, concentrated, and dried in vacuo to give a pale yellow solid(116 mg, 100%). MS (ESI) m/z: 506.1 (M+H)⁺.

97D.(S)-3-(2-(4-(2-(Aminomethyl)-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)benzoicacid: 97C (115 mg, 0.227 mmol) was dissolved in water and NH₄OH (2:1; 12mL). To it was added catalytic amount of Raney Ni. The mixture wasplaced on a hydrogenation apparatus under 55 psi for 48 h. The catalystwas removed by filtration. The filtrate was concentrated to give a whitesolid (116 mg, 100% yield). MS (ESI) m/z: 510.1 (M+H)⁺.

97E. To a solution of BOP (0.195 g, 0.440 mmol) and DMAP (0.108 g, 0.880mmol) in DCM (30 mL) and DMF (3.00 mL) at rt was added a solution of 97D(0.112 g, 0.22 mmol) and DIPEA (0.115 mL, 0.660 mmol) in DMF (7 mL) viaa syringe pump over 7.5 h. To the mixture was added 0.5N HCl (30 mL),and the mixture was stirred for 10 min. The two layers were separatedand the aqueous layer was extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated. Itwas purified by reverse phase HPLC to give the desired product (0.120 g,90% yield) as a white solid. MS (ESI) m/z: 492.0 (M+H)⁺.

97F. Example 97 was prepared following the procedures described in step3C, by replacing 3B with 97E; followed by step 1G. ¹H NMR (400 Hz,MeOH-d₄) δ ppm 9.58-9.50 (2H, m), 8.00 (1H, d, J=2.01 Hz), 7.69 (2H, dd,J=8.53, 2.26 Hz), 7.52-7.64 (5H, m), 7.46-7.34 (3H, m), 7.15 (1H, d,J=15.56 Hz), 6.81 (1H, d, J=15.56 Hz), 5.85 (1H, s), 4.93 (1H, m),4.14-4.02 (2H, m), 3.76 (3H, s), 3.48-3.57 (1H, m), 3.35 (1H, td,J=3.14, 1.25 Hz). MS (ESI) m/z: 624.0 (M+H)⁺. Analytical HPLC: RT=4.85min.

Example 98 1 TFA Salt

98A. To a solution 97E (15 mg, 0.025 mmol) in acetonitrile (1.5 mL) wasadded NCS (3.97 mg, 0.030 mmol). The reaction mixture was cooled to0-10° C., and TEA (5.18 μL, 0.037 mmol) was added. The color of thereaction changed from colorless to light brown-yellow solution upon thebase addition. The reaction was completed in 10 min. The mixture wasconcentrated, and purified through normal phase chromatography to givethe 98A (5.5 mg, 42.2% yield) as a colorless oil. MS (ESI) m/z: 526.2(M+H)⁺.

98B. Example 98 was prepared following the procedures described in step3C, by replacing 3B with 98A; followed by step 1G. ¹H NMR (400 MHz,MeOH-d₄)) δ ppm 9.53 (1H, s), 9.45 (1H, s), 8.02 (1H, s), 7.67 (1H, dd,J=8.53, 2.26 Hz), 7.58 (3H, d, J=8.53 Hz), 7.41-7.51 (3H, m), 7.31 (2H,s), 7.14 (1H, d, J=15.56 Hz), 6.83 (1H, d, J=15.81 Hz), 5.82 (1H, s),4.85-4.89 (1H, m), 3.93-4.03 (2H, m), 3.75 (3H, s), 3.15-3.27 (2H, m).MS (ESI) m/z: 658.1 (M+H)⁺. Analytical HPLC: RT=6.97 min.

Example 99 1 TFA Salt

99A. Methyl 2-fluoro-5-formylbenzoate: To a solution of2-fluoro-5-formylbenzoic acid (1.0 g, 5.65 mmol) in toluene (27 mL) andMeOH (9.14 mL, 226 mmol) was added (diazomethyl)trimethylsilane (4.24mL, 8.48 mmol) dropwise at rt. The reaction mixture was stirred underargon at rt for 50 min. The solvent was removed to give a white solid(1.05 g, 100% yield). MS (ESI) m/z: 183.1 (M+H)⁺.

99B. (E)-Methyl5-(2-(tert-butoxycarbonylamino)-3-methoxy-3-oxoprop-1-enyl)-2-fluorobenzoate:To a mixture of 99A (1.05 g, 6.04 mmol) and methyl2-(tert-butoxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (1.984 g,6.34 mmol) was added DCM (30.2 mL). It was cooled to 0° C., and DBU(1.183 mL, 7.85 mmol) was added. The mixture was warmed up to rt, andstirred for 12 h. The reaction mixture was diluted with DCM, andquenched with aq. NH₄Cl. The organic layer was washed with water andbrine, dried over Na₂SO₄, concentrated, and dried in vacuo to give thedesired product (2.3 g, 97% yield) as a yellow oil. MS (ESI) m/z: 254.2(M-Boc+H)⁺.

99C. (S)-Methyl5-(2-(tert-butoxycarbonylamino)-3-methoxy-3-oxopropyl)-2-fluorobenzoate:99B (2.3 g, 6.04 mmol) was dissolved in MeOH (30.2 mL) and(+)-1,2-bis((2S,5S)-2,5-diethyphospholano)benzene(cyclooctadien)rhodium(I) trifluoromethanesulfonate (0.153 g, 0.211 mmol) was added. Thereaction mixture was placed on a hydrogenation apparatus under 50 psifor 48 h. The solvent was removed to give a light-brown oil which wasused directly in the next step (2.4 g, 100% yield). MS (ESI) m/z: 256.1(M-Boc+H)⁺.

99D.(S)-2-(tert-Butoxycarbonylamino)-3-(4-fluoro-3-(methoxycarbonyl)phenyl)propanoicacid: A mixture of 99C (1.5 g, 3.80 mmol), MeOH (7 mL), potassiumcarbonate (0.788 g, 5.70 mmol), and water (7.00 mL) was heated to refluxfor 3.5 h. The reaction was diluted with water (50 mL) and extractedwith DCM. The aqueous layer was acidified with concentrated HCl to pH 2,and extracted with EtOAc. Combined extract was washed with brine, driedover Na₂SO₄, concentrated, and dried in vacuo to give 99D (910 mg, 59.7%yield) as a yellow solid. MS (ESI) m/z: 242.1 (M-Boc+H)⁺.

99E. Example 99 was prepared following the procedures described in step2A, by replacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with99D and by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate14; followed by steps 2B; 2G; 97E; 3C; and 1G. ¹H NMR (400 MHz,MeOH-d₄)) δ ppm 9.52 (s, 1H) 8.01 (d, J=2.01 Hz, 1H) 7.67-7.74 (m, 3H)7.53-7.63 (m, 4H) 7.30 (t, J=8.91 Hz, 2H) 7.16 (d, J=15.56 Hz, 1H) 6.78(d, J=15.56 Hz, 1H) 5.80 (m, 1H) 4.51 (d, J=14.05 Hz, 1H) 4.09 (d,J=14.05 Hz, 1H) 3.74 (s, 3H) 3.35 (dt, J=3.26, 1.63 Hz, 1H) 3.16-3.26(m, 1H) 2.76 (s, 3H). MS (ESI) m/z: 656.1 (M+H)⁺. Analytical HPLC:RT=5.53 min.

Example 100 1 TFA Salt

Example 100 was prepared following the procedures described in 98A, byreplacing TEA with DIPEA, and by replacing 97E with Example 99. ¹H NMR(400 MHz, MeOH-d₄)) δ ppm 9.50-9.56 (m, 1H) 8.02 (d, J=2.01 Hz, 1H)7.64-7.70 (m, 3H) 7.58 (d, J=8.53 Hz, 1H) 7.45-7.52 (m, 2H) 7.17-7.27(m, 2H) 7.13 (d, J=15.56 Hz, 1H) 6.81 (d, J=15.56 Hz, 1H) 5.87 (dd,J=6.27, 1.76 Hz, 1H) 4.67 (dd, J=12.05, 4.52 Hz, 1H) 4.53 (d, J=13.80Hz, 1H) 3.97 (d, J=13.80 Hz, 1H) 3.76 (s, 3H) 3.33-3.38 (m, 1H) 3.13 (t,J=12.05 Hz, 1H) 2.77 (s, 3H). MS (ESI) m/z: 690.0 (M+H)⁺. AnalyticalHPLC: RT=7.76 min.

Example 101 1 TFA Salt

101A.{3-Bromo-4-[2-[(S)-2-(3-bromo-phenyl)-1-tert-butoxycarbonylamino-ethyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-3-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid and byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 8;followed by steps 2B; and 1C. MS (ESI) m/z: 725.0 (M+H)⁺.

101B.{3-Allyl-4-[2-[(S)-2-(3-allyl-phenyl)-1-tert-butoxycarbonylamino-ethyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-phenyl}-carbamicacid methyl ester: To a 5 mL microwave vial was placed 101A (110 mg,0.152 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg,1.518 mmol), THF (1.5 mL), potassium carbonate (420 mg, 3.04 mmol),water (1.2 ml), and PdCl₂(dppf)-CH₂Cl₂Adduct (24.80 mg, 0.030 mmol). Thevial was purged with argon for several minutes and sealed. The resultedmixture was heated in a microwave oven at 120° C. for 12 min. Themixture was concentrated and purified by reverse phase chromatography togive 101B (30 mg, 30.5% yield) as a brown oil. MS (ESI) m/z: 647.3(M+H)⁺.

101C. Example 101 was prepared following the procedures described instep 2E/2F, by replacing 2D with 101B; followed by steps 2G; 1F, byreplacing ethanol with methanol as the solvent; and 1G. ¹H NMR (400 MHz,CD₃OD) δ ppm 9.53 (1H, s), 8.01 (1H, d, J=2.26 Hz), 7.70 (1H, dd,J=8.53, 2.26 Hz), 7.59-7.62 (1H, m), 7.41 (1H, s), 7.39 (1H, s), 7.35(1H, dd, J=8.28, 2.26 Hz), 7.24-7.31 (2H, m), 7.18 (1H, d, J=10.29 Hz),7.15 (1H, d, J=3.01 Hz), 7.08 (1H, d, J=7.53 Hz), 6.79 (1H, d, J=15.81Hz), 6.46 (1H, s), 5.10 (1H, dd, J=11.80, 4.77 Hz), 3.73 (3H, s), 3.52(1H, dd, J=12.67, 4.89 Hz), 3.10-3.17 (1H, m), 2.51-2.63 (3H, m), 2.36(1H, s), 1.73 (2H, s), 1.22 (1H, s), 0.96 (1H, s). MS (ESI) m/z: 623.2(M+H)⁺. Analytical HPLC: RT=6.99 min.

Example 102 1 TFA Salt

Example 102 was prepared following the procedures described in 98A, byreplacing TEA with DIPEA, and by replacing 97E with Example 101. ¹H NMR(400 MHz, MeOH-d₄)) δ ppm 9.54 (1H, s), 8.02 (1H, d, J=2.26 Hz),7.65-7.70 (1H, m), 7.57-7.61 (1H, m), 7.35 (1H, d, J=1.51 Hz), 7.29 (1H,dd, J=8.16, 2.13 Hz), 7.23 (1H, t, J=7.53 Hz), 7.18 (1H, d, J=4.52 Hz),7.14-7.16 (1H, m), 7.06 (1H, d, J=8.28 Hz), 7.02 (1H, d, J=7.53 Hz),6.81 (1H, d, J=15.56 Hz), 6.39 (1H, s), 4.92-4.98 (1H, m), 3.73 (3H, s),3.25-3.28 (1H, m), 3.08-3.15 (1H, m), 2.54-2.65 (2H, m), 2.51 (1H, m),2.30 (1H, m), 1.76 (2H, m), 1.20 (1H, m), 0.96 (1H, m). MS (ESI) m/z:657.1 (M+H)⁺. Analytical HPLC: RT=9.39 min.

Example 103 1 TFA Salt

103A.(4-{2-[(S)-2-(3-Bromo-phenyl)-1-tert-butoxycarbonylamino-ethyl]-1H-imidazol-4-yl}-3-nitro-phenyl)-carbamicacid methyl ester: This compound was prepared following the proceduresdescribed in step 2A, by replacing(S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-3-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid and byreplacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 9;followed by step 2B. MS (ESI) m/z: 560.0 (M+H)⁺.

103B. (S,E)-Methyl3-(3-(2-(tert-butoxycarbonylamino)-2-(4-(4-(methoxycarbonylamino)-2-nitrophenyl)-1H-imidazol-2-yl)ethyl)phenyl)acrylate:A mixture of 103A (180 mg, 0.321 mmol), methyl acrylate (0.087 mL, 0.964mmol), tri-o-tolylphosphine (39.1 mg, 0.128 mmol), diacetoxypalladium(21.63 mg, 0.096 mmol), and DIEA (0.196 mL, 1.124 mmol) in Acetonitrile(0.5 mL) was degassed and purged with argon. It was placed in amicrowave oven at 150° C. for 9 min. The catalyst was filtered-off andrinsed with EtOAc. The filtrate was concentrated and purified by normalphase chromatography to give 103B as an orange oil (130 mg, 71.6%yield). MS (ESI) m/z: 566.1 (M+H)⁺.

103C. Example 103 was prepared following the procedures described instep 2G, by replacing 2E with 103B, by replacing methanol with THF, andby replacing the hydrogen balloon with hydrogen (55 psi); followed bysteps 97C; 97E by using the syringe pump addition over 4 h; 3C; and 1G.¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1H) 7.99 (d, J=2.26 Hz, 1H)7.66-7.71 (m, 1H) 7.58-7.61 (m, 1H) 7.56 (d, J=1.76 Hz, 1H) 7.29-7.36(m, 3H) 7.23-7.27 (m, 2H) 7.12-7.18 (m, 2H) 6.76 (d, J=15.56 Hz, 1H)6.53 (s, 1H) 5.08 (dd, J=11.54, 4.52 Hz, 1H) 3.74 (s, 3H) 3.43-3.49 (m,1H) 3.07-3.15 (m, 1H) 2.88-2.94 (m, 1H) 2.82-2.87 (m, 1H) 2.70-2.82 (m,1H) 2.47-2.55 (m, 1H). MS (ESI) m/z: 638.2 (M+H)⁺. Analytical HPLC:RT=5.59 min.

Example 104 1 TFA Salt

Example 104 was prepared following the procedures described in step 2A,by replacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-3-(3-bromo-4-fluoro-phenyl)-2-tert-butoxycarbonylamino-propionicacid and by replacing 2-bromo-1-(2-bromophenyl)ethanone withIntermediate 9; followed by steps 2B; 103B; 2G, by replacing methanolwith THF, and by replacing the hydrogen balloon with hydrogen (55 psi);97C; 97E by using the syringe pump addition over 4 h; 3C; and 1G. ¹H NMR(400 MHz, CD₃OD) δ ppm 9.51 (s, 1H) 7.99 (d, J=2.26 Hz, 1H) 7.69 (dd,J=8.53, 2.26 Hz, 1H) 7.58-7.62 (m, 1H) 7.54 (d, J=1.76 Hz, 1H) 7.33-7.38(m, 1H) 7.23-7.32 (m, 3H) 7.07-7.17 (m, 2H) 6.75 (d, J=15.56 Hz, 1H)6.56 (dd, J=7.03, 2.26 Hz, 1H) 5.06 (dd, J=11.67, 4.89 Hz, 1H) 3.75 (s,3H) 3.42-3.49 (m, 1H) 2.90-3.25 (m, 2H) 2.71-2.82 (ddd, J=15.50, 7.72,2.38 Hz, 2H) 2.54 (ddd, J=15.37, 10.85, 2.38 Hz, 1H). MS (ESI) m/z:656.3 (M+H)⁺. Analytical HPLC: RT=5.69 min.

Example 105 2 TFA Salt

Example 105 was prepared following the procedures described in step 2A,by replacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with(S)-3-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propionic acidand by replacing 2-bromo-1-(2-bromophenyl)ethanone with Intermediate 9;followed by steps 2B; 103B; 2G, by replacing methanol with THF, and byreplacing the hydrogen balloon with hydrogen (55 psi); 97C; 97E by usingthe syringe pump addition over 4 h; 3C; and 1G. ¹H NMR (400 MHz, CD₃OD)δ ppm 9.42 (s, 1H) 7.87 (d, J=2.26 Hz, 1H) 7.48-7.59 (m, 4H) 7.20-7.27(m, 2H) 7.10-7.17 (m, 2H) 7.04-7.07 (m, 1H) 6.62 (d, J=15.56 Hz, 1H)5.46 (dd, J=10.79, 4.77 Hz, 1H) 3.65 (s, 3H) 3.50-3.59 (m, 1H) 3.36-3.44(m, 1H) 3.02-3.09 (m, 1H) 2.98 (dd, J=8.03, 2.51 Hz, 1H) 2.83-2.93 (m,1H) 2.66-2.75 (m, 1H). MS (ESI) m/z: 639.2 (M+H)⁺. Analytical HPLC:RT=4.75 min.

Example 106 2 TFA Salt

106A. Diethyl2-acetamido-2-((6-bromo-5-fluoropyridin-2-yl)methyl)malonate:2-Bromo-3-fluoro-6-methylpyridine (2.24 g, 11.79 mmol), NBS(2.34 g,13.15 mmol), CCl₄ (40 mL), and AIBN (0.10 g, 0.609 mmol) were addedtogether and heated to reflux under argon for 4.5 h. The CCl₄ wasremoved. The residue was dissolved in EtOAc and washed with water andbrine. It was dried over Na₂SO₄, and concentrated to give2-bromo-6-(bromomethyl)-3-fluoropyridine which was used in the next stepwithout purification. MS (ESI) m/z: 269.9 (M+H)⁺. NaH (0.707 g of 60%dispersion, 17.69 mmol) was placed in a three-neck flask with 15 mL ofDMF. It was cooled in an ice-bath. A solution of diethyl2-acetamidomalonate (3.59 g, 11.79 mmol) in 15 mL of DMF was addeddropwise via an additional funnel White foam formed and the mixture wasstirred in the ice-bath for 20 minutes after the addition. A solution of2-bromo-6-(bromomethyl)-3-fluoropyridine in 10 mL of DMF was addedthrough an additional funnel dropwise. The ice-bath was removed and itwas stirred at rt under argon for 2 h. It was quenched with water andextracted with EtOAc. The EtOAc solution was washed with water andbrine, dried over Na₂SO₄, and concentrated. It was purified by normalphase chromatography to give 106A as an off-white solid (2.39 g, 50%).MS (ESI) m/z: 405.0 (M+H)⁺.

106B. 2-Amino-3-(6-bromo-5-fluoropyridin-2-yl)propanoic acid: 106A (2.36g, 5.82 mmol) was suspended in 20 mL of water and 20 ml of 48% aqueousHBr was added. The mixture was heat to reflux under argon for 7 h. Thesolvent was removed to give 106B as an off-white solid (1.80 g, 100%yield). This material was used in the next step without furtherpurification. MS (ESI) m/z: 263.0 (M+H)⁺.

106C.3-(6-Bromo-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoicacid: 106B (1.53 g, 5.82 mmol) was added with 30 mL of dioxane. Aqueous1N NaOH (30 mL) was added to form a light yellow solution. To it wasadded di-tert-butyl dicarbonate (2.3 g, 10.54 mmol). The mixture wasstirred at rt under argon. After 30 minutes, the mixture became thickand it was hard to stir. More dioxane (20 mL) was added and the mixturewas stirred for 2.5 h. The dioxane was removed. The pH of the aqueoussolution was adjusted to about 4 with 1N HCl. It was then extracted withEtOAc. The EtOAc extract was washed with brine, dried over Na₂SO₄, andconcentrated to give 106C as an off-white solid (1.86 g, 86%). MS (ESI)m/z: 263.0 (M+H-Boc)⁺.

106D. tert-ButylN-{19-fluoro-11-[(methoxycarbonyl)amino]-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-3-yl}carbamate:This compound was prepared following the procedures described in step2A, by replacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with106C and by replacing 2-bromo-1-(2-bromophenyl)ethanone withIntermediate 9; followed by the steps 2B; 103B; 2G, by replacingmethanol with THF and by replacing the hydrogen balloon with hydrogen(55 psi); 97C; and 97E, by using the syringe pump addition over 4 h. MS(ESI) m/z: 525.2 (M+H)⁺.

106E. Methyl N-{3-amino-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate:This compound was prepared following the procedure described in 3C, byreplacing 3B with 106D. MS (ESI) m/z: 425.2 (M+H)⁺.

106F. Example 106: This compound was prepared following the proceduredescribed in 1G by replacing 1F with 106E. ¹H NMR (400 MHz, CD₃OD) δ ppm9.43 (s, 1H) 9.41 (s, 1H) 7.86 (d, J=2.26 Hz, 1H) 7.58 (dd, J=8.53, 2.26Hz, 1H) 7.47-7.52 (m, 2H) 7.31-7.37 (m, 1H) 7.18-7.27 (m, 3H) 7.14 (s,1H) 7.08 (d, J=15.81 Hz, 1H) 6.60 (d, J=15.56 Hz, 1H) 5.44 (dd, J=11.04,4.77 Hz, 1H) 3.66 (s, 3H) 3.51-3.58 (m, 1H) 3.37-3.45 (m, 1H) 3.02-3.13(m, 1H) 2.86-2.96 (m, 2H) 2.71-2.80 (m, 1H). MS (ESI) m/z: 657.2 (M+H)⁺.Analytical HPLC: RT=5.52 min.

Example 107 Enantiomer A, 2 TFA Salt Example 108 Enantiomer B, 2 TFASalt

Example 106 was separated by Chiral HPLC (CHIRALCEL® OD-H ODH,Isocratic, 70% B over 20 min. A=Heptane with 0.1% DEA, B=MeOH/EtOH(50:50) with 0.1% DEA) to give Example 107 and Example 108. Example 107:¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 9.03 (s, 1H) 8.83 (d, J=8.03 Hz,1H) 7.78-7.81 (m, 2H) 7.49-7.55 (m, 2H) 7.42 (d, J=8.53 Hz, 1H)7.18-7.26 (m, 3H) 7.00-7.06 (m, 2H) 6.97 (d, J=15.56 Hz, 1H) 6.58 (d,J=15.56 Hz, 1H) 5.74 (td, J=8.85, 5.65 Hz, 1H) 3.62 (s, 3H) 3.37-3.47(m, 2H) 2.92-3.04 (m, 2H) 2.82-2.92 (m, 1H) 2.77 (td, J=7.72, 3.39 Hz,1H). MS (ESI) m/z: 657.2 (M+H)⁺. Analytical HPLC: RT=5.35 min. Example108: ¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 9.03 (s, 1H) 8.78 (d,J=8.03 Hz, 1H) 7.76-7.84 (m, 2H) 7.49-7.55 (m, 2H) 7.42 (d, J=8.53 Hz,1H) 7.18-7.26 (m, 3H) 7.00-7.06 (m, 2H) 6.97 (d, J=15.56 Hz, 1H) 6.58(d, J=15.56 Hz, 1H) 5.74 (td, J=8.85, 5.65 Hz, 1H) 3.61 (s, 3H)3.37-3.47 (m, 2H) 2.92-3.04 (m, 2H) 2.82-2.92 (m, 1H) 2.76 (td, J=7.72,3.39 Hz, 1H). MS (ESI) m/z: 657.2 (M+H)⁺. Analytical HPLC: RT=5.46 min.

Example 109 1 TFA Salt

Example 109 was prepared following the procedures described in step 2A,by replacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with4-((S)-2-tert-Butoxycarbonylamino-2-carboxy-ethyl)-benzoic acid methylester and by replacing 2-bromo-1-(2-bromophenyl)ethanone withIntermediate 8; followed by steps 2B; 97B-E; 3C; and 1G. ¹H NMR (400MHz, CD₃OD) δ ppm 9.54 (1H, s), 8.02 (1H, d, J=2.26 Hz), 7.90 (2H, d,J=8.28 Hz), 7.71 (1H, dd, J=8.53, 2.26 Hz), 7.59-7.63 (1H, m), 7.43 (2H,s), 7.31-7.37 (3H, m), 7.16-7.25 (2H, m), 6.81 (1H, d, J=15.56 Hz), 5.35(1H, dd, J=12.05, 5.27 Hz), 3.68-3.78 (2H, m), 3.64 (3H, s), 3.35 (1H,ddd, J=3.58, 2.26, 1.94 Hz), 3.23-3.27 (1H, m). MS (ESI) m/z: 624.3(M+H)⁺. Analytical HPLC: RT=5.92 min.

Example 110 1 TFA Salt

Example 110 was prepared following the procedures described in 98A, byreplacing TEA with DIPEA, and by replacing 97E with Example 109. ¹H NMR(400 MHz, CD₃OD) δ ppm 9.54 (1H, s), 8.03 (1H, d, J=2.01 Hz), 7.84 (2H,d, J=8.28 Hz), 7.65-7.71 (1H, m), 7.57-7.61 (1H, m), 7.27-7.38 (4H, m),7.15-7.21 (2H, m), 6.84 (1H, d, J=15.56 Hz), 5.19 (1H, dd, J=11.80, 5.02Hz), 3.63 (3H, s), 3.45-3.51 (2H, m), 3.17-3.27 (2H, m). MS (ESI) m/z:659.1 (M+H)⁺. Analytical HPLC: RT=8.58 min.

Example 111 1 TFA Salt

Example 111 was prepared following the procedures described in Example101, by replacing(S)-3-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid with(S)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid in101A. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (1H, s), 8.01 (1H, d, J=2.26Hz), 7.69 (1H, dd, J=8.53, 2.26 Hz), 7.58-7.62 (1H, m), 7.44 (1H, d,J=1.00 Hz), 7.26-7.32 (4H, m), 7.09-7.18 (2H, m), 6.98 (1H, s), 6.77(1H, d, J=15.56 Hz), 6.71 (1H, d, J=1.00 Hz), 5.15 (1H, dd, J=11.29,6.53 Hz), 3.73 (3H, s), 3.65-3.40 (2H, dd, J=12.42, 6.65 Hz), 3.07 (1H,t, J=12.05 Hz), 2.79 (1H, m), 2.60 (1H, m), 1.86-1.98 (3H, m), 1.63-1.70(1H, m), 1.39-1.50 (1H, m). MS (ESI) m/z: 623.1 (M+H)⁺. Analytical HPLC:RT=7.09 min.

Example 112 1 TFA Salt

112A.3-(2-{4-[2-(2-Benzyloxycarbonylamino-acetylamino)-4-nitro-phenyl]-pyridin-2-yl}-2-tert-butoxycarbonylamino-ethyl)-benzoicacid methyl ester: This compound was prepared by following theprocedures described in step 89B, by replacing 89A with Intermediate 16;followed by step 10D, by replacing but-3-enoic acid with2-(benzyloxycarbonylamino)acetic acid and by replacing Hunig's base withTEA. MS (ESI) m/z: 684.3 (M+H)⁺.

112B.3-(2-{4-[4-Amino-2-(2-benzyloxycarbonylamino-acetylamino)-phenyl]-pyridin-2-yl}-2-tert-butoxycarbonylamino-ethyl)-benzoicacid methyl ester: To a solution of 112A (87 mg, 0.127 mmol) in MeOH (10mL) were added NH₄Cl (68.1 mg, 1.272 mmol) and 5 nCl₂.2H₂O (144 mg,0.636 mmol) at rt. The reaction was stirred under argon at rt for 5 h.The solid was filtered off and the solvent was removed to give 112B as ayellow solid in quantitative yield. MS (ESI) m/z: 654.3 (M+H)⁺.

112C. Example 112 was prepared following the procedures described instep 89E, by replacing 89D with 112B; followed by steps 72B; 2G; 94D;3C; and 1G. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.52 (s, 1H), 8.88-8.35 (m,2H), 7.99 (d, J=1.9 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.59 (t,J=9.8 Hz, 2H), 7.55-7.35 (m, 4H), 7.37-7.21 (m, 1H), 7.14 (t, J=13.8 Hz,2H), 6.83 (d, J=15.2 Hz, 1H), 6.73-6.21 (m, 1H), 5.36 (dd, J=11.9, 5.4Hz, 1H), 4.37-3.80 (m, 1H), 3.75 (s, 3H), 3.42-3.20 (m, 2H). LC-MS (ESI)m/z: 678.2 (M+H)⁺. Analytical HPLC: RT=6.258 min.

Example 114 1 TFA Salt

Example 114 was prepared following the procedures described in step 10D,by replacing 10C with 52F and by replacing but-3-enoic acid with3-vinylbenzoic acid; followed by steps 2E/2F; 2G; 10H; and 1G. ¹H NMR(400 MHz, CD₃OD) δ ppm 9.36-9.68 (m, 2H) 8.23 (br. s., 1H) 7.83-8.03 (m,1H) 7.08-7.76 (m, 10H) 6.95 (br. s., 1 H) 5.49 (s, 1H) 3.87-4.18 (m, 2H)3.66-3.89 (m, 3H) 2.64-2.95 (m, 2H) 1.99-2.22 (m, 1H) 1.71-1.92 (m, 1H).MS (ESI) m/z: 668.4 (M+H)⁺. Analytical HPLC: RT=6.75 min.

Example 139(2E)-3-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-N-{19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-3-yl}prop-2-enamide,2 TFA salt

139A. Ethyl3-(6-bromo-5-fluoropyridin-2-yl)-2-(diphenylmethyleneamino)propanoate:139A was prepared by following a literature procedure (Ansari, A. M. etal., Synthetic Communications, 38:2330-2340 (2008)) using2-bromo-6-(bromomethyl)-3-fluoropyridine synthesized according to theprocedure described in 106A. MS (ESI) m/z: 455.1(M+H)⁺.

139B. Ethyl3-(6-bromo-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoate.To a flask containing 139A (1.703 g, 3.74 mmol) in water (10 mL) wasadded TFA (5.0 mL, 64.9 mmol) at rt. The reaction was stirred underargon at rt for 3 h. Solvent was removed to give a brown oil. MS (ESI)m/z: 292.9 (M+H)⁺. To a suspension of the above oil in ethyl acetate (30mL) were added TEA (2.61 mL, 18.70 mmol) and BOC₂O (0.955 mL, 4.11 mmol)at rt. The reaction was stirred under argon at rt for 1.5 h.

The reaction mixture was diluted with EtOAc, washed with 1M HCl, satNaHCO₃ and brine. The organic phase was dried over magnesium sulfate,filtered and concentrated. The crude product was purified by normalphase chromatography to give 139B (884 mg, 60% overall yield over 4steps from 2-bromo-3-fluoro-6-methylpyridine) as a tan oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.33 (1H, d, J=8.03 Hz), 7.12 (1H, dd, J=8.03, 3.26Hz), 5.37 (1H, d, J=5.77 Hz), 4.62 (1H, d, J=6.02 Hz), 4.15-4.28 (2H,m), 3.28 (2H, d, J=3.76 Hz), 1.42 (9H, s), 1.26 (3H, t, J=7.03 Hz). ¹⁹FNMR (376 MHz, CDCl₃) δ ppm −115.64 (1F, s). MS (ESI) m/z: 391.0/393.0(M+H)⁺.

139C. (E)-tert-Butyl3-(6-(2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)-3-fluoropyridin-2-yl)acrylate.139C was prepared following the procedure described in 103B by replacingmethyl acrylate with tert-butyl acrylate. ¹H NMR (400 MHz, CDCl₃) δ ppm7.77 (1H, dd, J=15.56, 1.51 Hz), 7.34 (1H, dd, J=9.54, 8.53 Hz), 7.12(1H, dd, J=8.41, 3.64 Hz), 6.92 (1H, d, J=15.56 Hz), 5.67 (1H, d, J=7.53Hz), 4.57-4.77 (1H, m), 4.07-4.25 (2H, m), 3.21-3.42 (2H, m), 1.54 (9H,s), 1.43 (9H, s), 1.23 (3H, t, J=7.03 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δppm −127.70 (1F, s). MS (ESI) m/z: 439.1 (M+H)⁺.

139D.3-(6-(3-tert-Butoxy-3-oxopropyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoicacid. To a solution of 139C (0.68 g, 1.551 mmol) in THF (10 mL) andwater (3 mL) was added LiOH (0.074 g, 3.10 mmol) at 0° C. The reactionwas stirred under argon at 0° C. for 2 hrs. 1.0 N HCl (3.1 mL) was addedto neutralize the reaction. The reaction mixture was diluted with EtOAc,washed with H₂O and brine. The organic phase was dried over magnesiumsulfate, filtered and concentrated to give a tan solid of(E)-3-(6-(3-tert-butoxy-3-oxoprop-1-enyl)-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoicacid. MS (ESI) m/z: 411.1 (M+H)⁺. To the above obtained intermediatewere added catalytic amount of 10% Pd/C and MeOH (15 mL). The reactionmixture was stirred under a hydrogen balloon at rt for 1 h. Catalyst wasfiltered off and solvent was removed to give 139D as a tan solid. MS(ESI) m/z: 413.1 (M+H)⁺.

139E. tert-Butyl3-(6-(2-(tert-butoxycarbonylamino)-2-(4-(2-nitrophenyl)-1H-imidazol-2-yl)ethyl)-3-fluoropyridin-2-yl)propanoate.139A was prepared following the procedure described in 2A and 2B byreplacing (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with 139D in2A.

139F.3-(6-(2-(tert-Butoxycarbonylamino)-2-(4-(2-nitrophenyl)-1H-imidazol-2-yl)ethyl)-3-fluoropyridin-2-yl)propanoicacid. To a solution of 139E (220 mg, 0.396 mmol) in DCM (7 mL) was addedTFA (3.0 mL, 38.9 mmol) at rt. The reaction was stirred under argon atrt for 1.5 h. Solvent was removed to give a brown solid, which was usedwithout further purification. MS (ESI) m/z: 400.1 (M+H)⁺. The aboveobtained product was dissolved in dioxane (15 mL), to which were addedNaOH (1.980 mL, 1.980 mmol) and BOC₂O (0.138 mL, 0.594 mmol) at rt.After stirred for 2 h, MS showed the reaction was complete. The reactionmixture was diluted with EtOAc, washed with 1M HCl and brine. Theorganic phase was dried over magnesium sulfate, filtered andconcentrated to give 139F as a tan oil. MS (ESI) m/z: 500.1 (M+H)⁺.

139G.3-(6-(2-(4-(2-Aminophenyl)-1H-imidazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)-3-fluoropyridin-2-yl)propanoicacid, TFA salt. 139G was prepared according to the procedure describedin 15B. The crude product was purified by reverse phase chromatographyto give 139G as a brown solid. MS (ESI) m/z: 470.1 (M+H)⁺.

139H. Example 139 was prepared following the procedure described in 23E,1G and 3C, by replacing 23D with 139G. ¹H NMR (400 MHz, CD₃OD) δ ppm9.50 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.67 (1H, dd, J=8.53, 2.26 Hz),7.56-7.61 (1H, m), 7.48-7.54 (1H, m), 7.41-7.48 (2H, m), 7.34-7.40 (1H,m), 7.25-7.34 (3H, m), 7.18 (1H, d, J=15.56 Hz), 6.70 (1H, d, J=15.56Hz), 5.55 (1H, dd, J=11.04, 4.77 Hz), 3.59-3.70 (1H, m), 3.46-3.57 (1H,m), 3.12-3.21 (1H, m), 2.94-3.07 (2H, m), 2.80-2.90 (1H, m). ¹⁹F NMR(376 MHz, CD₃OD) δ ppm −77.55 (11.8 F, s, TFA), −130.00 (1F, s).

MS (ESI) m/z: 584.2 (M+H)⁺. Analytical HPLC: RT=5.756 min.

Example 140 MethylN-{3-[(2E)-3-(2-acetyl-5-chlorophenyl)prop-2-enamido]-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 140 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with Intermediate 4and by using EDC, HOBt, and triethylamine. ¹H NMR (400 MHz, CD₃OD) δ ppm9.42 (s, 1H) 7.89 (d, J=15.81 Hz, 1H) 7.79 (d, J=8.28 Hz, 1H) 7.53 (d,J=2.01 Hz, 1H) 7.47 (d, J=1.76 Hz, 1H) 7.41 (dd, J=8.28, 2.01 Hz, 1H)7.29-7.36 (m, 1H) 7.19-7.27 (m, 3H) 7.14 (s, 1H) 6.39 (d, J=15.56 Hz,1H) 5.48 (dd, J=11.04, 4.77 Hz, 1H) 3.64 (s, 3H) 3.52-3.60 (m, 1H) 3.42(dd, J=14.18, 11.17 Hz, 1H) 3.03 (d, J=10.04 Hz, 1H) 2.84-2.95 (m, 2H)2.70-2.80 (m, 1H) 2.48 (s, 3H). MS (ESI) m/z: 631.2 (M+H)⁺. AnalyticalHPLC: RT=6.0 min.

Example 141 MethylN-{3-[(2E)-3-(2-acetyl-5-chloro-6-fluorophenyl)prop-2-enamido]-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 141 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with Intermediate 18and by using EDC, HOBt, and triethylamine. ¹H NMR (400 MHz, CD₃OD) δ ppm7.68-7.76 (m, 2H) 7.60-7.67 (m, 2H) 7.43-7.50 (m, 1H) 7.33-7.41 (m, 3H)7.28 (s, 1H) 6.64 (dd, J=16.06, 2.01 Hz, 1H) 5.61 (dd, J=11.29, 4.77 Hz,1H) 3.78 (s, 3H) 3.65-3.73 (m, 1H) 3.55 (dd, J=14.18, 11.17 Hz, 1H)3.14-3.24 (m, 1H) 2.98-3.09 (m, 2H) 2.84-2.93 (m, 1H) 2.61 (s, 3H). MS(ESI) m/z: 649.2 (M+H)⁺. Analytical HPLC: RT=6.1 min.

Example 142 MethylN-{3-[(2,6-difluoro-4-methylbenzene)amido]-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 142 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with2,6-difluoro-4-methylbenzoic acid and by using EDC, HOBt, andtriethylamine ¹H NMR (400 MHz, CD₃CN) δ ppm 7.86 (s, 1H) 7.43 (d, J=1.76Hz, 1H) 7.27-7.34 (m, 1H) 7.22-7.27 (m, 2H) 7.16 (dd, J=8.41, 3.89 Hz,1H) 7.11-7.13 (m, 1H) 6.78 (d, J=9.03 Hz, 2H) 5.78-5.85 (m, 1H) 3.62 (s,3H) 3.52 (d, J=7.78 Hz, 2H) 2.98-3.08 (m, 1H) 2.89-2.97 (m, 1H)2.72-2.84 (m, 2H) 2.26 (s, 3H). MS (ESI) m/z: 579.1 (M+H)⁺. AnalyticalHPLC: RT=5.6 min.

Example 143 MethylN-{19-fluoro-3-[(4-methylcyclohexane)amido]-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 143 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with(1r,4r)-4-methylcyclohexanecarboxylic acid and by using EDC, HOBt, andtriethylamine. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.60 (d, J=1.25 Hz, 1H)7.42-7.49 (m, 1H) 7.34-7.39 (m, 2H) 7.29-7.34 (m, 1H) 7.25 (s, 1H) 5.44(dd, J=11.54, 4.77 Hz, 1H) 3.78 (s, 3H) 3.54-3.63 (m, 1H) 3.46 (dd,J=14.05, 11.54 Hz, 1H) 3.14-3.23 (m, 1H) 2.97-3.07 (m, 2H) 2.83-2.91 (m,1H) 2.22 (ddd, J=12.23, 8.85, 3.51 Hz, 1H) 1.75-1.86 (m, 3H) 1.42-1.52(m, 2H) 1.32-1.42 (m, 1H) 0.95-1.06 (m, 2H) 0.92 (d, J=6.53 Hz, 3H). MS(ESI) m/z: 549.2 (M+H)⁺. Analytical HPLC: RT=6.0 min.

Example 146(2E)-N-{6-Chloro-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-3-yl}-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamide,2 TFA salt

Example 146 was prepared following the procedure described in Example 9,by replacing Example 8 with Example 139 and by running the reaction atrt. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.51 (1H, s), 7.98 (1H, d, J=2.26 Hz),7.66 (1H, dd, J=8.53, 2.26 Hz), 7.57 (1H, d, J=8.53 Hz), 7.50 (1H, dd,J=7.65, 1.38 Hz), 7.38-7.47 (2H, m), 7.33 (1H, td, J=7.59, 1.38 Hz),7.30 (1H, dd, J=7.91, 0.88 Hz), 7.23 (1H, dd, J=8.28, 3.76 Hz), 7.17(1H, d, J=15.56 Hz), 6.75 (1H, d, J=15.56 Hz), 5.49 (1H, dd, J=10.16,4.64 Hz), 3.52 (1H, dd, J=14.31, 4.52 Hz), 3.44 (1H, dd, J=14.31, 10.29Hz), 3.03-3.17 (2H, m), 2.91 (2H, t, J=6.02 Hz). MS (ESI) m/z: 618.1(M+H)⁺. Analytical HPLC: RT=7.368 min.

Example 147 MethylN-{3-[(2E)-3-(3-chloro-2,6-difluorophenyl)prop-2-enamido]-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 147 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with Intermediate 15and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm9.55 (s, 1H) 7.68 (d, J=16.06 Hz, 1H) 7.53-7.63 (m, 2H) 7.43-7.50 (m,1H) 7.32-7.41 (m, 3H) 7.28 (s, 1H) 7.09-7.16 (m, 1H) 7.01 (d, J=16.06Hz, 1H) 5.61 (dd, J=11.29, 4.77 Hz, 1H) 3.78 (s, 3H) 3.69 (dd, J=14.18,4.64 Hz, 1H) 3.55 (dd, J=14.05, 11.29 Hz, 1H) 3.14-3.25 (m, 1H)2.98-3.09 (m, 2H) 2.85-2.93 (m, 1H). MS (ESI) m/z: 625.1 (M+H)⁺.Analytical HPLC: RT=6.07 min.

Example 148 MethylN-{6-chloro-19-fluoro-15-oxo-3-[(2E)-3-(3-chloro-2,6-difluorophenyl)prop-2-enamido]-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

148A. tert-ButylN-{6-chloro-19-fluoro-11-[(methoxycarbonyl)amino]-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-3-yl}carbamate:This compound was prepared by following the procedure described inExample 9, by replacing Example 8 with 106D and lowering the reactiontemperature to 10-20 deg. MS (ESI) m/z: 559.1(M+H)⁺.

148B. MethylN-{3-amino-6-chloro-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate:This compound was prepared by following the procedure described in 3C,by replacing 3B with 148A. MS (ESI) m/z: 459.1(M+H)⁺.

148C. Example 148 was prepared following the procedure described in 1G,by replacing 1F with 148B, by replacing Intermediate 1 with Intermediate15 and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δppm 7.56 (d, J=16.06 Hz, 1H) 7.40-7.51 (m, 2H) 7.27-7.37 (m, 2H) 7.20(ddd, J=14.81, 8.53, 3.01 Hz, 2H) 6.95-7.03 (m, 1H) 6.90 (d, J=16.06 Hz,1H) 5.41 (dd, J=10.79, 4.52 Hz, 1H) 3.66 (s, 3H) 3.44-3.51 (m, 1H)3.31-3.41 (m, 1H) 3.01-3.11 (m, 1H) 2.97 (d, J=7.28 Hz, 1H) 2.74-2.86(m, 2H). MS (ESI) m/z: 659.1 (M+H)⁺. Analytical HPLC: RT=8.05 min.

Example 149 MethylN-{6-chloro-3-[(2,6-difluoro-4-methylbenzene)amido]-19-fluoro-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 149 was prepared following the procedure described in 1G, byreplacing 1F with 148B, by replacing Intermediate 1 with2,6-difluoro-4-methylbenzoic acid and by using EDC, HOBt, and Hunig'sbase. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.61 (d, J=1.76 Hz, 1H) 7.41-7.50(m, 2H) 7.29-7.39 (m, 2H) 6.92 (d, J=9.03 Hz, 2H) 5.61 (dd, J=11.29,5.02 Hz, 1H) 3.78 (s, 3H) 3.53-3.64 (m, 2H) 3.11-3.21 (m, 1H) 2.99-3.10(m, 1H) 2.87-2.98 (m, 2H) 2.40 (s, 3H). MS (ESI) m/z: 613.1 (M+H)⁺.Analytical HPLC: RT=7.12 min.

Example 150 MethylN-{6-chloro-19-fluoro-3-[(4-methylcyclohexane)amido]-15-oxo-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl}carbamate,2 TFA salt

Example 150 was prepared following the procedure described in 1G, byreplacing 1F with 148B, by replacing Intermediate 1 with(1r,4r)-4-methylcyclohexanecarboxylic acid and by using EDC, HOBt, andHunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.61 (s, 1H) 7.42-7.49 (m,1H) 7.32-7.41 (m, 2H) 7.29 (dd, J=8.28, 3.76 Hz, 1H) 5.33 (dd, J=11.04,4.77 Hz, 1H) 3.78 (s, 3H) 3.47-3.57 (m, 1H) 3.40 (dd, J=14.05, 11.04 Hz,1H) 3.13-3.23 (m, 1H) 2.96-3.06 (m, 2H) 2.80-2.89 (m, 1H) 2.18-2.28 (m,1H) 1.86 (s, 1H) 1.74-1.83 (m, 3H) 1.44-1.53 (m, 2H) 1.35-1.42 (m, 1H)0.95-1.06 (m, 2H) 0.92 (d, J=6.53 Hz, 3H). MS (ESI) m/z: 583.1 (M+H)⁺.Analytical HPLC: RT=7.47 min.

Example 151 2 TFA Salt

Example 151 was prepared following the procedure described in Example 9by replacing Example 8 with 107 and lowering the reaction temperature to10-20 deg. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.53 (s, 1H) 7.99 (d, J=2.26Hz, 1H) 7.65-7.70 (m, 1H) 7.57-7.62 (m, 2H) 7.37-7.47 (m, 2H) 7.31-7.35(m, 1H) 7.27 (dd, J=8.28, 3.76 Hz, 1H) 7.19 (d, J=15.56 Hz, 1H) 6.76 (d,J=15.56 Hz, 1H) 5.49 (dd, J=10.54, 4.77 Hz, 1H) 3.74-3.80 (m, 3H)3.52-3.59 (m, 1H) 3.42-3.50 (m, 1H) 3.12-3.21 (m, 1H) 3.03 (s, 1H)2.86-2.96 (m, 2H). MS (ESI) m/z: 691.1 (M+H)⁺. Analytical HPLC: RT=6.93min.

Example 157 2 TFA Salt

Example 157 was prepared following the procedures described in 1G, byreplacing 1F with 148B, by replacing Intermediate 1 with Intermediate 4and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm7.98 (d, J=15.81 Hz, 1H) 7.87 (d, J=8.53 Hz, 1H) 7.62 (d, J=2.01 Hz, 1H)7.56 (d, J=2.01 Hz, 1H) 7.49 (dd, J=8.28, 2.01 Hz, 1H) 7.39-7.45 (m, 1H)7.33-7.38 (m, 1H) 7.26-7.32 (m, 2H) 6.50 (d, J=15.56 Hz, 1H) 5.49 (dd,J=10.54, 4.77 Hz, 1H) 3.73 (s, 3H) 3.52-3.61 (m, 1H) 3.40-3.49 (m, 1H)3.09-3.19 (m, 1H) 2.91-3.03 (m, 2H) 2.79-2.89 (m, 1H) 2.55-2.60 (m, 3H).MS (ESI) m/z: 665.1 (M+H)⁺. Analytical HPLC: RT=7.38 min.

Example 158 2 TFA Salt

Example 158 was prepared following the procedures described in 1G, byreplacing 1F with 148B, by replacing Intermediate 1 with Intermediate 18and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm7.56-7.66 (m, 2H) 7.49-7.55 (m, 2H) 7.29-7.38 (m, 2H) 7.19-7.26 (m, 2H)6.55 (dd, J=16.06, 2.01 Hz, 1H) 5.42 (dd, J=10.79, 4.52 Hz, 1H) 3.67 (s,3H) 3.45-3.54 (m, 1H) 3.33-3.42 (m, 1H) 3.05 (d, J=1.76 Hz, 1H)2.90-2.98 (m, 1H) 2.83 (ddd, J=19.20, 8.66, 2.76 Hz, 2H) 2.50 (s, 3H).MS (ESI) m/z: 683.1 (M+H)⁺. Analytical HPLC: RT=7.56 min.

Example 162 2 TFA Salt

Example 162 was prepared following the procedures described in 1G, byreplacing 1F with 148B. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.40 (s, 1H) 7.85(d, J=2.26 Hz, 1H) 7.51-7.57 (m, 1H) 7.44-7.49 (m, 2H) 7.23-7.34 (m, 2H)7.13-7.22 (m, 2H) 7.05 (d, J=15.56 Hz, 1H) 6.62 (d, J=15.56 Hz, 1H) 5.33(dd, J=10.67, 4.64 Hz, 1H) 3.64 (s, 3H) 3.40-3.47 (m, 1H) 3.28-3.37 (m,1H) 2.98-3.09 (m, 1H) 2.85-2.95 (m, 1H) 2.79-2.84 (m, 1H) 2.70-2.77 (m,1H). MS (ESI) m/z: 691.0 (M+H)⁺. Analytical HPLC: RT=7.13 min.

Example 163 2 TFA Salt

Example 163 was prepared following the procedure described in 1G, byreplacing 1F with 106E, by replacing Intermediate 1 with Intermediate 19and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm7.92 (d, J=15.56 Hz, 1H) 7.75 (s, 1H) 7.54-7.62 (m, 2H) 7.47-7.53 (m,1H) 7.38-7.45 (m, 1H) 7.29-7.36 (m, 3H) 7.24 (s, 1H) 6.97 (s, 1H) 6.67(d, J=15.56 Hz, 1H) 5.59 (dd, J=10.92, 4.89 Hz, 1H) 3.74 (s, 3H)3.61-3.69 (m, 1H) 3.49-3.59 (m, 1H) 3.10-3.20 (m, 1H) 2.94-3.05 (m, 2H)2.80-2.89 (m, 1H). MS (ESI) m/z: 639.1 (M+H)⁺. Analytical HPLC: RT=6.74min.

Example 164 2 TFA Salt

Example 164 was prepared following the procedures described in 1G, byreplacing 1F with 148B, by replacing Intermediate 1 with Intermediate 19and by using EDC, HOBt, and Hunig's base. ¹H NMR (400 MHz, CD₃OD) δ ppm7.95 (d, J=15.56 Hz, 1H) 7.80 (s, 1H) 7.58-7.65 (m, 2H) 7.50-7.58 (m,1H) 7.40-7.47 (m, 2H) 7.34 (dd, J=8.53, 2.26 Hz, 1H) 7.27 (dd, J=8.28,3.76 Hz, 1H) 7.03 (m, 1H) 6.73 (d, J=15.56 Hz, 1H) 5.56 (dd, J=10.29,4.52 Hz, 1H) 3.77 (s, 3H) 3.54-3.62 (m, 1H) 3.45-3.53 (m, 1H) 3.10-3.21(m, 2H) 2.92-2.98 (m, 2H). MS (ESI) m/z: 673.0 (M+H)⁺. Analytical HPLC:RT=8.73 min.

Example 165 2 TFA Salt

165A. 2-Bromo-1-(2-bromo-4-fluorophenyl)ethanone. To a 20 mL microwavevial was added of 1-(2-bromo-4-fluorophenyl)ethanone (1.15 g, 5.19mmol), copper(II) bromide (2.320 g, 10.39 mmol), and ethyl acetate (12ml) The mixture (suspension) was heated in microwave at 120° C. for 17min (fixed hold time). Reaction was filtered via Buchner funnel toremove solid. The solid was rinsed with EtOAc. The clear, green filtratewas washed with water (2×10 mL), brine, dried over anh. Na₂SO₄, filteredand concentrated, and purified through normal phase chromatography togive 165A (1.02 g, 66.4% yield) as a colorless oil. MS (ESI) m/z: 295.0(M−H).

165B. Benzyl3-(6-bromo-5-fluoropyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoate.To a clear, pale yellow solution of 106C (1.3 g, 3.58 mmol) in MeOH(13.5 mL)/Water (1.485 mL) was added Cesium carbonate (0.676 g, 2.076mmol). The reaction was stirred for 20 min at rt. The solvent wasremoved, and remaining water in the cesium salt of SM was furtherreduced by repeated azeotropic distillation with toluene. The resultingdry salt was dissolved in DMF(10 mL). (bromomethyl)benzene (0.553 mL,4.65 mmol) was added, and the resulting mixture was stirred at rt underAr. for 2 hrs. To the reaction mixture was added ice-cold water, andthen extracted with EtOAc. The organic layer was washed with water (2×),brine (1×), dried over anh. Na₂SO₄, filtered, concentrated, and purifiedthrough normal phase chromatography to give 165B (1.62 g, 100% yield) asa colorless oil. MS (ESI) m/z: 453.0 (M+H)⁺.

165C. (E)-Methyl3-(6-(3-(benzyloxy)-2-(tert-butoxycarbonylamino)-3-oxopropyl)-3-fluoropyridin-2-yl)acrylate.This compound was prepared following the procedure described in 103B, byreplacing 103A with 165B. MS (ESI) m/z: 459.1 (M+H)⁺.

165D.2-(tert-Butoxycarbonylamino)-3-(5-fluoro-6-(3-methoxy-3-oxopropyl)pyridin-2-yl)propanoicacid. This compound was prepared following the procedure described in10F, by replacing 10E with 165C and by replacing the hydrogen balloonwith hydrogen (55 psi). MS (ESI) m/z: 371.1 (M+H)⁺.

165E. 2-(2-Bromo-4-fluorophenyl)-2-oxoethyl2-(tert-butoxycarbonylamino)-3-(5-fluoro-6-(3-methoxy-3-oxopropyl)pyridin-2-yl)propanoate.This compound was prepared following the procedure described in 2A, byreplacing (5)-2-(tert-butoxycarbonylamino)pent-4-enoic acid with 165Dand by replacing 2-bromo-1-(2-bromophenyl)ethanone with 165A. MS (ESI)m/z: 585.0 (M+H)⁺.

165F. tert-ButylN-(11,19-difluoro-15-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-3-yl)carbamate.This compound was prepared following the procedures described in 2B, byreplacing 2A with 165E; 10B; 10C; 97C; 97E. MS (ESI) m/z: 600.2 (M+H)⁺.

165G.3-Amino-11,19-difluoro-5,14,22,23-tetraazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-15-one.This compound was prepared following the procedures described in 10H byreplacing 10G with 165F. MS (ESI) m/z: 370.0 (M+H)⁺.

165H. Example 165: This compound was prepared following the proceduresdescribed in 1G by replacing 1F with 165G. ¹H NMR (400 MHz, CD₃OD) δ ppm9.58 (s, 1H) 8.04 (d, J=2.26 Hz, 1H) 7.74 (dd, J=8.53, 2.26 Hz, 1H)7.63-7.68 (m, 1H) 7.48-7.58 (m, 2H) 7.34-7.41 (m, 2H) 7.15-7.27 (m, 3H)6.79 (d, J=15.56 Hz, 1H) 5.60 (dd, J=11.04, 4.77 Hz, 1H) 3.67-3.76 (m,1H) 3.58 (dd, J=14.05, 11.29 Hz, 1H) 3.19-3.28 (m, 1H) 3.02-3.14 (m, 2H)2.87-2.96 (m, 1H). MS (ESI) m/z: 602.1 (M+H)⁺. Analytical HPLC: RT=5.98min.

Example 166 2 TFA Salt

Example 166 was prepared following the procedures described in 1G byreplacing 1F with 165G, and by replacing Intermediatel with Intermediate3. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.59 (s, 1H) 7.83-7.89 (m, 1H)7.48-7.58 (m, 3H) 7.38 (dd, J=8.41, 3.64 Hz, 1H) 7.35 (s, 1H) 7.11-7.22(m, 3H) 6.80 (d, J=15.81 Hz, 1H) 5.59 (dd, J=11.17, 4.89 Hz, 1H)3.65-3.74 (m, 1H) 3.52-3.61 (m, 1H) 3.18-3.28 (m, 1H) 3.02-3.13 (m, 2H)2.87-2.96 (m, 1H). MS (ESI) m/z: 620.0 (M+H)⁺. Analytical HPLC: RT=5.97min.

Unless otherwise stated, the compounds listed in the following tablescan be prepared by one skilled in the art of organic synthesis using theprocedures described above.

TABLE III-1 Examples III-1 to III-15:

LCMS HPLC [M + RT Ex. # R R³ R^(6a) H]⁺ (min.) III-1 (S)

Cl F 636.0 7.78 III-2 (S)

Cl NHCO₂Me 597.1 8.32 III-3 (S)

Cl NHCO₂Me 629.0 7.19 III-4 (S)

Cl NHCO₂Me 665.0 7.39 III-5 (R)

Cl NHCO₂Me 665.0 7.28 III-6 (S)

Cl NHCO₂Me 689.2 8.17 III-7 (S)

Cl NHCO₂Me 659.0 7.95 III-8 (R)

Cl NHCO₂Me 659.0 7.96 III-9 (S)

Cl NHCO₂Me 613.0 7.45 III-10 (R)

Cl NHCO₂Me 613.0 7.42 III-11

Cl NHCO₂Me 648.2 7.46 III-12

Cl NHCO₂Me 637.2 8.03 III-13

H NHCO₂Me 671.3 6.13 III-14 (R)

Cl NHCO₂Me 648.2 7.87 III-15 (S)

Cl NHCO₂Me 648.2 7.89

TABLE III-2 Examples III-16 to III-21:

LCMS HPLC [M + RT Ex. # R R³ R^(6a) H]⁺ (min.) III-16

H F 588.1 6.67 III-17

Cl NHCO₂Me 677.1 7.33 III-18 (R)

Cl NHCO₂Me 677.2 7.77 III-19 (S)

Cl NHCO₂Me 677.2 7.77 III-20 (R)

Cl NHMe 633.2 6.45 III-21 (S)

Cl NHMe 633.2 6.43III-30. MethylN-[(3S)-3-[(2E)-3-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamido]-20-(dimethylamino)-15-oxo-5,14,19,22,23-pentaazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl]carbamate

III-30A. (E)-Methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(dimethylamino)pyrimidine-4-carboxylate:To a solution of methyl2-chloro-6-)dimethylamino)pyrimidine-4-carboxylate (0.8 g, 3.71 mmol) inCH₃CN (10 mL) was added tert-butyl acrylate (1.62 mL, 11.13 mmol), DIEA(2.59 mL, 14.84 mmol), tri-o-tolylphosphine (0.34 g, 1.11 mmol), andpalladium acetate (0.167 g, 0.74 mmol). The reaction was heated in amicrowave oven at 145° C. for 10 min. The mixture was diluted withEtOAc, filtered through CELITE®, washed CELITE® with EtOAc, andconcentrated. Purification by normal phase chromatography gave(E)-methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(dimethylamino)pyrimidine-4-carboxylate(680 mg, 60% yield). MS (ESI) m/z: 308.2 (M+H)⁺.

III-30B. (E)-tert-Butyl3-(4-(dimethylamino)-6-(hydroxymethyl)pyrimidin-2-yl)acrylate:(E)-Methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(dimethylamino)pyrimidine-4-carboxylate(1.91 g, 6.21 mmol) was suspended with diethyl ether (50 mL). Solidlithium borohydride (0.165 g, 6.84 mmol) was added portion wise. Themixture was stirred at RT under argon for 10 min. The color of themixture changed from yellow to orange. The reaction was cooled to 0-10°C. and stirred for 1 h. It was quenched with water. EtOAc was added andthe mixture was stirred for 20 min. The two layers were separated. Theorganic layer was washed with water and brine, dried over sodiumsulfate, concentrated, and dried under vacuum to giving the desiredproduct (1.72 g, 6.16 mmol, 99% yield) as a yellow solid. MS (ESI) m/z:280.2 (M+H)⁺.

III-30C. (E)-tert-Butyl3-(4-(dimethylamino)-6-formylpyrimidin-2-yl)acrylate: (E)-tert-Butyl3-(4-(dimethylamino)-6-(hydroxymethyl)pyrimidin-2-yl)acrylate (1.72 g,6.16 mmol) was dissolved in ethyl acetate (Volume: 50 mL). Dess-MartinPeriodinane (3.40 g, 8.00 mmol) was added. The mixture was stirred at RTunder argon for 20 min, and then at 0-10° C. for 20 min. To the reactionmixture was added another 50 mg of Dess-Martin periodinane. The reactionwas stirred at 10° C.-20° C. for 30 min. It was filtered through CELITE®and washed CELITE® with EtOAc. The EtOAc solution was concentrated.Purification by normal phase chromatography gave the title compound (1.3g, 76% yield). MS (ESI) m/z: 310.2 (M+H+MeOH)⁺.

III-30D. Methyl2-(benzyloxycarbonylamino)-3-(2-((E)-3-tert-butoxy-3-oxoprop-1-enyl)-6-(dimethylamino)pyrimidin-4-yl)acrylate:Cbz-phosphonoglycine (1.660 g, 5.01 mmol) was dissolved in CH₂Cl₂ (12mL) and cooled in an ice-bath. DBU (1.511 mL, 10.02 mmol) was added andthe mixture was stirred for 5 minutes. A slurry of (E)-tert-butyl3-(4-(dimethylamino)-6-formylpyrimidin-2-yl)acrylate (1.39 g, 5.01 mmol)in DCM (12.00 mL) was added. The ice-bath was removed and the mixturewas stirred at RT under argon for 1.5 h. The reaction mixture wasdiluted with CH₂Cl₂, washed with water and brine, dried over sodiumsulfate, concentrated, and purified by normal phase chromatographygiving the desired product (MS (ESI) m/z: 483.3 (M+H)⁺.

III-30E. (S)-Methyl2-(benzyloxycarbonylamino)-3-(2-(3-tert-butoxy-3-oxopropyl)-6-(dimethylamino)pyrimidin-4-yl)propanoate:Methyl2-(benzyloxycarbonylamino)-3-(2-((E)-3-tert-butoxy-3-oxoprop-1-enyl)-6-(dimethylamino)pyrimidin-4-yl)acrylate(2.0 g, 4.14 mmol) was suspended in MeOH (50 mL), and [S,S] Et DuPhosRh[I] (0.150 g, 0.207 mmol) was added. The mixture was purged with N₂and then placed under 55 psi of H₂ for 22 hrs. The suspension changed toclear solution after 3 hrs. It was concentrated and dried under vacuumto give the desired product (2.017 g, 4.14 mmol, 100% yield). MS (ESI)m/z: 487.3 (M+H)⁺.

III-30F.(S)-2-(Benzyloxycarbonylamino)-3-(2-(3-tert-butoxy-3-oxopropyl)-6-(dimethylamino)pyrimidin-4-yl)propanoicacid: (S)-Methyl2-(benzyloxycarbonylamino)-3-(2-(3-tert-butoxy-3-oxopropyl)-6-(dimethylamino)pyrimidin-4-yl)propanoate(2.014 g, 4.14 mmol) was dissolved in THF (15 mL). A solution of lithiumhydroxide (0.218 g, 9.11 mmol) in water (5.00 mL) was added. The mixturewas stirred at RT under argon for 1.5 h. To the reaction mixture wasadded 1N HCl to adjust the pH to ˜7. The THF was removed and it wasextracted with EtOAc. The combined organic mixture was dried over sodiumsulfate, concentrated, and dried under vacuum to give the desiredproduct (2.1 g, 3.93 mmol, 95% yield) as a yellow foam. MS (ESI) m/z:473.3 (M+H)⁺.

III-30G. (S)-2-(2-Bromo-4-(methoxycarbonylamino)phenyl)-2-oxoethyl2-(benzyloxycarbonylamino)-3-(2-(3-tert-butoxy-3-oxopropyl)-6-(dimethylamino)pyrimidin-4-yl)propanoate:To a clear solution of(S)-2-(benzyloxycarbonylamino)-3-(2-(3-tert-butoxy-3-oxopropyl)-6-(dimethylamino)pyrimidin-4-yl)propanoicacid (2.1 g, 4.00 mmol) in DMF (16.00 ml) was added KHCO₃ (0.521 g, 5.20mmol) and water (0.2 mL). The reaction mixture was stirred for 20˜30 minat RT and then cooled to 0° C. A solution of methyl3-bromo-4-(2-bromoacetyl)phenylcarbamate (1.614 g, 4.60 mmol) in DMF (3mL) was added dropwise and the mixture was allowed to warm to RT over 20min. The reaction was stirred at RT for 80 min, and ice-water was addedto give a white suspension. The mixture was warmed to RT, and thenextracted with EtOAc. The organic layer was washed with water and brine,dried over sodium sulfate, filtered, concentrated, and dried undervacuum to give the desired product (3.6 g, 3.88 mmol, 97% yield) as ayellow foam. MS (ESI) m/z: 742.4 (M+H)⁺, 744.4 (M+2+H)⁺.

III-30H. (S)-tert-Butyl3-(4-(2-(benzyloxycarbonylamino)-2-(4-(2-bromo-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate:To the clear, yellow solution of the product from part III-30G (3.6 g,3.88 mmol) in toluene (50 mL) was added ammonium acetate (8.97 g, 116mmol). The reaction mixture was heated to reflux for 4 h. The reactionwas cooled to RT, diluted with EtOAc (500 mL) and then washed withsaturated sodium bicarbonate and brine. It was dried over sodiumsulfate, filtered, and concentrated to give a brown residue.Purification by normal phase chromatography afforded the desired product(0.97 g, 34.6%) as yellow foam. MS (ESI) m/z: 722.4 (M+H)⁺, 724.4(M+2+H)⁺.

III-30I. (S)-tert-Butyl3-(4-(2-(benzyloxycarbonylamino)-2-(4-(2-bromo-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate:(S)-tert-Butyl3-(4-(2-(benzyloxycarbonylamino)-2-(4-(2-bromo-4-(methoxycarbonylamino)phenyl)-1H-imidazol-2-yl)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate(610 mg, 0.844 mmol) was dissolved in THF (7035 μl) and cooled to 0° C.To the reaction was added N,N-dicyclohexylmethylamine (221 μl, 1.013mmol) followed by dropwise (over 5 min) addition of SEM-Cl (284 μl,1.604 mmol). The reaction mixture was allowed warm to RT and stirred atRT for 70 min. It was quenched with water, and concentrated to removethe THF. The residue was dissolved in ethyl acetate and washed withaqueous sodium bicarbonate, water, and then brine. The organic layer wasdried over sodium sulfate, concentrated, and dried under vacuum to givethe desired product (0.85 g, 118% yield) as a yellow viscous oil. MS(ESI) m/z: 854.5 (M+H)⁺.

III-30J. (S)-tert-Butyl3-(4-(2-(4-(2-amino-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-(benzyloxycarbonylamino)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate,2 TFA salt: (S)-tert-Butyl3-(4-(2-(benzyloxycarbonylamino)-2-(4-(2-bromo-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate(72 mg, 0.084 mmol) was dissolved in DMSO (1 ml). L-Proline (5.83 mg,0.051 mmol), Copper(I) iodide (4.82 mg, 0.025 mmol), and potassiumcarbonate (35.0 mg, 0.253 mmol) were added. The mixture was purged withargon for a few minutes and ammonium hydroxide (9.86 μl, 0.253 mmol) wasadded. The mixture was sealed and heated at 70° C. in an oil-bath for 3h. The product was purified by reverse phase chromatography (17.17 mg,20% yield) as a brown oil. MS (ESI) m/z: 789.7 (M+H)⁺.

III-30K.(S)-3-(4-(2-(4-(2-Amino-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-(benzyloxycarbonylamino)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoicacid, 2 TFA salt: (S)-tert-Butyl3-(4-(2-(4-(2-amino-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-(benzyloxycarbonylamino)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoate,2 TFA (120 mg, 0.118 mmol) and L-cysteine (71.5 mg, 0.590 mmol) weredissolved in DCM (5 ml)/TFA (1.667 ml). The mixture was stirred at RTunder Ar for 1 h. the mixture was concentrated, and purified by reversephase chromatography (65 mg, 57.3% yield) as a light brown oil. MS (ESI)m/z: 733.6 (M+H)⁺.

III-30L. MethylN-[(3S)-3-[(2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamido]-20-(dimethylamino)-15-oxo-5,14,19,22,23-pentaazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl]carbamate:To a solution of BOP (74.8 mg, 0.169 mmol) and DMAP (34.7 mg, 0.284mmol) in DCM (25 mL) and DMF (2.5 mL) at RT was added a solution of(S)-3-(4-(2-(4-(2-amino-4-(methoxycarbonylamino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-(benzyloxycarbonylamino)ethyl)-6-(dimethylamino)pyrimidin-2-yl)propanoicacid, 2 TFA (65 mg, 0.068 mmol) and DIEA (0.083 mL, 0.473 mmol) in DMF(2 mL) via a syringe pump over 3.5 h. The mixture was stirred at RT for60 min. It was concentrated to remove DCM. The residue was partitionedbetween EtOAc/water. The two layers were separated. The organic layerwas washed with water, concentrated, and purified by reverse phasechromatography (25 mg, 44.6% yield) as a white solid. MS (ESI) m/z:715.6 (M+H)⁺.

III-30M. MethylN-[(3S)-3-amino-20-(dimethylamino)-15-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,14,19,22,23-pentaazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl]carbamate:The product from part III-30L (20 mg, 0.024 mmol) was dissolved in MeOH(3 mL). Catalytic amount of Pd 10% activated carbon (3 mg) was added.The mixture was placed under a balloon of H₂ for 70 min. It was filteredto remove the catalyst. The filtrate was concentrated and dried undervacuum to give the desired product (14.71 mg, 74.6% yield) as a solid.MS (ESI) m/z: 581.5 (M+H)⁺.

III-30N. MethylN-[(3S)-3-amino-20-(dimethylamino)-15-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,14,19,22,23-pentaazatetracyclo[16.3.1.1̂{4,7}.0̂{8,13}]tricosa-1(22),4(23),6,8,10,12,18,20-octaen-11-yl]carbamate: Themixture of the product from part III-30M (10 mg, 0.017 mmol) and HCl(0.6 mL, 2.400 mmol) (4M in 1,4-dioxane) in a sealed tube was heated at65° C. for 1 h, and then cooled to RT. The suspension was dissolved inMeOH. It was concentrated, and dried under vacuum to give the desiredproduct (9.6 mg, 100% yield) as an off-white solid. MS (ESI) m/z: 451.4(M+H)⁺.

Example III-30: To a solution of the product from part III-30N (9.52 mg,17 mmol) in DMF (1 mL) was added (E)-2,5-dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (5.91 mg, 17 μmol) atRT, and then added DIPEA (0.036 mL, 0.204 mmol) dropwise at 0-10° C. Thecooling-bath was removed after 10 min, and reaction mixture was stirredat RT under argon for 2 h. The crude product was purified by reversephase chromatography (7.0 mg, 45.0% yield) as a white solid. ¹H NMR (400MHz, CD₃OD) δ ppm 9.56 (s, 1H) 8.03 (d, J=2.01 Hz, 1H) 7.68-7.77 (m, 2H)7.58-7.67 (m, 1H) 7.32-7.42 (m, 3H) 7.21 (d, J=15.56 Hz, 1H) 6.82-6.92(m, 2H) 5.51-5.62 (m, 1H) 3.76 (s, 3H) 3.51-3.62 (m, 1H) 3.22-3.31 (m,7H) 3.01-3.13 (m, 2H) 2.72-2.94 (m, 2H). MS (ESI) m/z: 683.5 (M+H)⁺.Analytical HPLC: RT=4.36 min.

TABLE III-3 Examples III-22 to III-30:

LCMS HPLC Ex. # R R³ R^(6a) R^(7a) [M + H]⁺ RT (min.) III-22

H NHCO₂Me Me 654.3 4.31 III-23 (S)

H NHCO₂Me Me 654.3 4.36 III-24 (S)

H NHCO₂Me Me 576.3 4.37 III-25 (S)

Cl NHCO₂Me Me 610.3 5.10 III-26 (S)

Cl NHCO₂Me Me 645.3 5.82 III-27 (S)

Cl NHCO₂Me Me 686.3 7.05 III-28 (S)

Cl NHCO₂Me Me 656.3 6.90 III-29 (S)

Cl NHCO₂Me Me 670.3 6.91 III-30 (S)

H NHCO₂Me N(Me)₂ 683.5 4.36

II-31. MethylN-{3-[(2E)-3-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamido]-19-fluoro-15-oxo-23-oxa-5,14,22-triazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4,6,8,10,12,18,20-octaen-1′-yl}carbamate

III-31A. 2-Amino-1-(2-bromo-4-nitrophenyl)ethanone, HCl salt: To asolution of 2-bromo-1-(2-bromo-4-nitrophenyl)ethanone (1.12 g, 3.47mmol) in acetonitrile (15 mL) was added sodium diformylamide (0.396 g,4.16 mmol) at RT. The reaction suspension was stirred under argon at RTfor 2 hrs. Then the reaction was warmed up and filtered. Solid waswashed with warm acetonitrile. Solvent was removed from filtrate to givea dark tar. LC-MS (ESI) m/z: 286.9 (M+H)⁺. To the above obtained productwas added 25 mL 4N HCl (aq.) solution and the mixture was heated up toreflux. After stirring for 1 hr, the reaction was allowed to stir at RTover night. Solvent was removed to give a yellow solid, which was usedwithout further purification. LC-MS (ESI) m/z: 258.9/261.0 (M+H)⁺.

III-31B. Methyl3-(6-(3-(2-(2-bromo-5-nitrophenyl)-2-oxoethylamino)-2-(tert-butoxycarbonylamino)-3-oxopropyl)-3-fluoropyridin-2-yl)propanoate:To a solution of2-(tert-butoxycarbonylamino)-3-(5-fluoro-6-(3-methoxy-3-oxopropyl)pyridin-2-yl)propanoicacid (393 mg, 1.061 mmol) in DMF (10 mL) were added EDC (264 mg, 1.379mmol) and HOBt (211 mg, 1.379 mmol), DIEA (0.185 mL mg, 1.061 mmol).After stirred at RT for 5 min, a solution of III-31A (314 mg, 1.061mmol) and DIEA (0.185 mL mg, 1.061 mmol) (prepared by adding DIEA intoamino ketone solution in 3 mL DMF, which turned dark immediately uponaddition of DIEA) was added at RT. The dark solution was stirred underargon at RT for 1 h. The reaction mixture was diluted with EtOAc, washedwith 1M HCl (1×15 mL) and brine (2×15 mL). The organic phase was driedover sodium sulfate, filtered and concentrated. The crude product waspurified by normal phase chromatography to give III-31B 145 mg (22.5%yield). LC-MS (ESI) m/z: 611.0/613.0 (M+H)⁺.

III-31C. Methyl3-(6-(2-(5-(2-bromo-4-nitrophenyl)oxazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)-3-fluoropyridin-2-yl)propanoate:To a solution of III-31B (145 mg, 0.237 mmol) in DCM (8 mL) was addedBurgess reagent (283 mg, 1.186 mmol) at RT. The reaction was stirredunder argon at RT and turned dark red. After stirred over night, thereaction was heated up to reflux (˜45° C. oil bath) for 2 hrs. Thereaction was cooled to RT. The reaction mixture was diluted with DCM,washed with H₂O and brine. The organic phase was dried over sodiumsulfate, filtered and concentrated. The crude product was purified bynormal phase chromatography to give III-31C 64 mg (46% yield) LC-MS(ESI) m/z: 593.0/594.9 (M+H)⁺.

III-31D. Methyl3-(6-(2-(5-(2-bromo-4-(methoxycarbonylamino)phenyl)oxazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)-3-fluoropyridin-2-yl)propanoate:To a solution of III-31C (64 mg, 0.108 mmol) in MeOH (5 mL) were addedNH₄Cl (57.7 mg, 1.079 mmol) and zinc dust (70.5 mg, 1.079 mmol) at RT.The reaction was stirred under argon at RT for 2.5 hrs. Solid wasfiltered and solvent was removed from filtrate to give a white solid.LC-MS (ESI) m/z: 563.0/565.0 (M+H)⁺. Thus obtained solid was dissolvedin DCM (10 mL), to which were added pyridine (0.044 mL, 0.539 mmol) andmethyl chloroformate (8.35 μL, 0.108 mmol) at 0° C. After stirred for 15min, water was added to quench the reaction. The reaction mixture wasdiluted with DCM, washed with 1M HCl and brine. The organic phase wasdried over sodium sulfate, filtered and concentrated. The crude productwas purified by normal phase chromatography to give III-31D 63.6 mg (95%yield). LC-MS (ESI) m/z: 621.0/623.0 (M+H)⁺.

III-31E. Methyl3-(6-(2-(5-(2-amino-4-(methoxycarbonylamino)phenyl)oxazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)-3-fluoropyridin-2-yl)propanoate:To a solution of III-31D (63 mg, 0.101 mmol) in DMSO (1.5 mL) were addedNaN₃ (19.77 mg, 0.304 mmol), L-proline (5.84 mg, 0.051 mmol), CuI (19.31mg, 0.101 mmol) and K₂CO₃ (42.0 mg, 0.304 mmol) at RT. The reaction wasstirred under argon at 90° C. After 11 hrs. The reaction was cooled toRT. The reaction mixture was diluted with EtOAc and water Ammoniumhydroxide solution was added to make the aqueous phase clear. Organicphase was separated and further washed with brine (2×). The organicphase was dried over sodium sulfate, filtered and concentrated to give asolid mixture of desired product and the corresponding azideintermediate in about 1:1 ratio 49 mg. LC-MS (ESI) m/z: 558.1 (M+H)⁺.

III-31F.3-(6-(2-(5-(2-Amino-4-(methoxycarbonylamino)phenyl)oxazol-2-yl)-2-(tert-butoxycarbonylamino)ethyl)-3-fluoropyridin-2-yl)propanoicacid, TFA salt: To a solution of III-32E in THF/H₂O was added LiOH(1.074 mg, 0.045 mmol) at 0° C. The reaction was stirred under argon at0° C. for 2 hrs. The reaction mixture was neutralized with 1.0M HCl andmost solvent was removed. The crude product was purified by reversephase chromatography to give III-31F 25 mg (85%). LC-MS (ESI) m/z: 544.1(M+H)⁺.

III-31G. tert-ButylN-{19-fluoro-11-[(methoxycarbonyl)amino]-15-oxo-23-oxa-5,14,22-triazatetracyclo[16.3.1.1^(4,7).0^(8,13)]tricosa-1(22),4,6,8,10,12,18,20-octaen-3-yl}carbamate:To a solution of DMAP (11.24 mg, 0.092 mmol) and BOP (61.0 mg, 0.138mmol) in DCM (40 mL) was added a solution of III-31F (25 mg, 0.046 mmol)and DIEA (0.040 mL, 0.230 mmol) in DMF (2 mL) at RT through a syringepump. After stirring over night, solvent was removed. The crude productwas purified by reverse phase chromatography to give III-31G 5.5 mg(23%). LC-MS (ESI) m/z: 526.1 (M+H)⁺.

Example III-31: To a solution of III-31G (5.5 mg, 10.47 μmol) in DCM(1.5 mL) was added TFA (0.5 mL, 6.49 mmol) at RT. The reaction wasstirred under argon at RT for 1 hr. Solvent was removed and residue wasdried in vacuo. Thus obtained intermediate was dissolved in DMF (1 mL),to which were added (E)-2,5-dioxopyrrolidin-1-yl3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate (3.64 mg, 10.47 μmol)and DIEA (0.05 mL, 0.286 mmol). The reaction was stirred at RT for 12hrs. The crude product was purified by reverse phase chromatography togive III-31 as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.43 (1H,s), 7.92 (1H, d, J=2.26 Hz), 7.58 (1H, dd, J=8.41, 2.13 Hz), 7.46-7.53(2H, m), 7.32 (1H, d, J=8.28 Hz), 7.27 (1H, dd, J=8.28, 1.76 Hz), 7.20(1H, t, J=8.91 Hz), 7.10 (1H, d, J=15.81 Hz), 7.00 (1H, s), 6.97 (1H,dd, J=8.66, 3.39 Hz), 6.69 (1H, d, J=15.56 Hz), 5.86 (1H, dd, J=10.16,4.89 Hz), 5.80-5.93 (1H, m), 3.66 (3H, s), 3.37-3.44 (2H, m), 3.29-3.35(2H, m), 3.16-3.19 (1H, m), 2.78-2.85 (1H, m). ¹⁹F NMR (376 MHz, CD₃OD)δ ppm)-77.21 (TFA, s), −130.84 (1F, s). LC-MS (ESI) m/z: 658.1 (M+H)⁺.Analytical HPLC: RT=7.681 min.

TABLE III-4 Examples III-31 to III-37: LCMS HPLC Ex. # Structure [M +H]+ RT (min) III-31

658.1 7.68 III-32

585.0 7.85 III-33

671.3 5.03 III-34

640.2 5.35 III-35

667.3 5.27 III-36

667.3 5.37 III-37

632.2 3.94

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: ring A is independently a C₃₋₁₀ carbocycle ora 5- to 10-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); ring Bis independently a benzene ring or a 5- to 6-membered heteroarylcomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); ring C is independently a benzene ring or a 5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); L₁ is independently selected fromthe group consisting of: a bond, —CHR⁵—, —CHR⁵CHR⁵—, —CR⁵═CR⁵—, —C≡C—,—OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—; L isindependently selected from the group consisting of: —C₁₋₆alkylene-(C₃₋₈ carbocycle)-C₀₋₄ alkylene-, and —C₁₋₆ alkylene-(5- to6-membered heterocycle)-C₀₋₄ alkylene-; wherein said heterocyclecomprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p); wherein said alkylene is substituted with 0-2R⁷ and optionally one or more of the carbon atoms of said alkylene maybe replaced by O, S, NH, N(C₁₋₄ alkyl), CO, CONH, NHCO, OCONH, NHCO₂,SO₂NH, NHSO₂, CON(C₁₋₄ alkyl), or N(C₁₋₄ alkyl)CO; wherein saidcarbocycle and heterocycle are substituted with 0-2 R^(7a); Y isindependently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄alkyl)-, —NHCONH—, —SO₂NH—, —NHCO₂—, and —NHSO₂—; R¹ is, independentlyat each occurrence, selected from the group consisting of: halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, OH, C₁₋₄haloalkyl, OCH₂F, OCHF₂,OCF₃, CN, NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂(C₁₋₄ alkyl),—CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄alkyl), —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄alkyl), —SO₂NH₂; —C(═NH)NH₂, and phenyl substituted with 0-2 R^(a); R²is independently a 5- to 7-membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p),wherein said heterocycle is substituted with 0-2 R^(2a); R^(2a) is,independently at each occurrence, selected from the group consisting of:halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃, OCF₃, CN, NH₂, CO₂H,CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), and —SO₂N(C₁₋₄alkyl)₂; R³ is independently selected from the group consisting of: H,halogen, OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H,CO₂(C₁₋₄ alkyl), —C(O)NH₂; —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂,—CH₂CO₂H, and C₃₋₆ cycloalkyl; R⁴ is independently selected from thegroup consisting of: H, and C₁₋₄ alkyl; R⁵ is, independently at eachoccurrence, selected from the group consisting of: H, halogen, OH, andC₁₋₄ alkyl; R⁶ is, independently at each occurrence, selected from thegroup consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄alkyl), NH₂, NH(C₁₋₄alkyl), —CH₂NH₂; —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —C(O)NH(CH₂)₂O(C₁₋₄alkyl),—CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and

R⁷ and R^(7a) are, independently at each occurrence, selected from thegroup consisting of: halogen, OH, NH₂, CH₂NH₂, CH₂F, CHF₂, CF₃, OCH₂F,OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH,CH₂O(C₁₋₄ alkyl), CH₂O(CH₂)₁₋₄O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl),CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂,—OCO(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,—(CO)₀₋₁(CH₂)₀₋₁—C₃₋₆ carbocycle, and —(CO)₀₋₁(CH₂)₀₋₁-(4- to 6-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein said carbocycle andheterocycle are substituted with 0-2 R⁸; R⁸ is, independently at eachoccurrence, selected from the group consisting of: halogen, OH, CHF₂,CF₃, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, and C₁₋₄ alkyl;R⁹ is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)), O,and S(O)_(p); R^(a) is, independently at each occurrence, selected fromthe group consisting of: halogen, OH, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl;p is, independently at each occurrence, selected from the groupconsisting of: 0, 1, and
 2. 2. The compound of claim 1, or astereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvatethereof, wherein: ring A is independently a 6-membered carbocycle, a 9-to 10-membered carbocycle, or a 5- to 10-membered heterocyclecomprising: carbon atoms and 1-3 heteroatoms selected from N, NH, N(C₁₋₄alkyl), O, and S(O)_(p); ring B is independently selected from the groupconsisting of: imidazole, oxazole, oxadiazole, triazole, pyridine,pyridazine, pyrimidine, and benzene; and ring C is independentlyselected from the group consisting of: benzene, pyridine, indazole,indole, benzimidazole, quinoline, isoquinoline and quinazoline.
 3. Thecompound of claim 1 or 2, or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate thereof, wherein: ring A isindependently selected from the group consisting of: benzene,cyclohexane, indane, tetrahydronaphthalene, naphthalene,dihydroisoxazole, isoxazole, pyrazole, imidazole, triazole, piperidine,indazole, indole, benzimidazole, quinoline, isoquinoline,tetrahydroquinoline, and tetrahydroisoquinoline;

is independently selected from the group consisting of:

and

is independently selected from the group consisting of:


4. A compound of Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein:

is independently selected from the group consisting of:

L₁ is independently selected from the group consisting of: a bond,—CHR⁵CHR⁵—, —CR⁵═CHR⁵—, —C≡C—, —OCH₂—, —CHR⁵NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NH—, and —CR⁵R⁵—; L is independently selected from thegroup consisting of: —C₁₋₆ alkylene-(C₃₋₈ carbocycle)-C₀₋₄ alkylene-,and —C₁₋₆ alkylene-(5- to 6-membered heterocycle)-C₀₋₄ alkylene-;wherein said heterocycle comprises: carbon atoms and 1-4 heteroatomsselected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein saidalkylene is substituted with 0-2 R⁷ and optionally one or more of thecarbon atoms of said alkylene may be replaced by O, S, NH, N(C₁₋₄alkyl), CO, CONH, NHCO, OCONH, SO₂NH, or CON(C₁₋₄ alkyl); wherein saidcarbocycle and heterocycle are substituted with 0-2 R^(7a); Y isindependently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —OCON(C₁₋₄alkyl)-, —NHCONH—, and —SO₂NH—; R¹ is, independently at each occurrence,selected from the group consisting of: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CN, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, CO₂(C₁₋₄ alkyl), CO(C₁₋₄ alkyl),—OCH₂CO₂H, —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CH₂NHCO₂(C₁₋₄ alkyl),—SO₂NH₂, and —C(═NH)NH₂; R² is independently a 5- to 6-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NH, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(2a); R^(2a) is, independently at each occurrence, selected from thegroup consisting of: halogen, C₁₋₄ alkyl, —CH₂OH, C₁₋₄ alkoxy, OH, CF₃,OCF₃, CN, NH₂, CO₂H, CO₂(C₁₋₄ alkyl), COC₁₋₄ alkyl, —CONH₂, —CONH(C₁₋₄alkyl), and —CON(C₁₋₄ alkyl)₂; R³ is independently selected from thegroup consisting of: H, halogen, OH, NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl),—C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H; R⁴ is independently selected from thegroup consisting of: H and C₁₋₄ alkyl; R⁵ is, independently at eachoccurrence, selected from the group consisting of: H, halogen, OH, andC₁₋₄ alkyl; R⁶ is, independently at each occurrence, selected from thegroup consisting of: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄alkyl), —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄alkyl), NH₂, NH(C₁₋₄alkyl), —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —C(O)NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, and

R⁷ and R^(7a) are, independently at each occurrence, selected from thegroup consisting of: halogen, OH, CHF₂, CF₃, N(C₁₋₄ alkyl)₂, C₁₋₄alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —OCO(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)(CH₂)₂N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, and—(CO)₀₋₁-(4- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R⁸; R⁸ is, independently ateach occurrence, selected from the group consisting of: halogen, OH,CHF₂, CF₃, C₁₋₄ alkoxy, and C₁₋₄ alkyl; and p is, independently at eachoccurrence, selected from the group consisting of: 0, 1, and
 2. 5. Thecompound of claim 4 having Formula (IIa) or Formula (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof.
 6. The compound of claim 4 having Formula (IIc) orFormula (IId):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof.
 7. The compound of any one of the preceding claimshaving Formula (I), (II), (IIa), (IIb), (IIc), or (IId), a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a solvate thereof,wherein: L₁ is independently selected from the group consisting of: abond, —CH₂CH₂—, —CH═CH—, —C(Me)=CH—, —C≡C—, and —CH₂NH—; L isindependently selected from the group consisting of:—(CH₂)₁₋₂-(phenylene)-(CH₂)₀₋₃—, —CH₂O(CH₂)₁₋₄-(phenylene)-(CH₂)₀₋₃—,—(CH₂)₁₋₂-(phenylene)-CONH(CH₂)₀₋₂—, —(CH₂)₁₋₂-phenylene-CON(C₁₋₄alkyl)(CH₂)₀₋₂—(CH₂)₁₋₂-(pyridinylene)-(CH₂)₀₋₃—,—CH₂-pyrimidinylene-(CH₂)₀₋₃—,

wherein each ring moiety is substituted with 0-2 R^(7a); Y isindependently selected from the group consisting of: CH₂, CH(C₁₋₄alkyl), C(C₁₋₄ alkyl)₂, O, S, NH, N(C₁₋₄ alkyl), N(CO₂(C₁₋₄ alkyl)),—CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and—SO₂NH—; R¹ is, independently at each occurrence, selected from:halogen, CN, OH, CH₂F, CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, —C(═NH)NH₂,—C(O)NH₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —SO₂NH₂; R³ isindependently selected from the group consisting of: H, halogen, OH,NH₂, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, —CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl),—C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, and —CH₂CO₂H; and R⁶is, independently at each occurrence, selected from the group consistingof: halogen, C₁₋₄ alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H,—(CH₂)₂CO₂H, —CH₂CO₂(C₁₋₄ alkyl), —(CH₂)₂CO₂(C₁₋₄ alkyl), NH₂, —CH₂NH₂,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), CONH₂, CONH(C₁₋₄ alkyl),CON(C₁₋₄ alkyl)₂, and


8. The compound of any one of the preceding claims having Formula (I),(II), (IIa), (IIb), (IIc), or (IId), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate thereof, wherein: L₁ isindependently selected from the group consisting of: a bond, —CH₂CH₂—and —CH═CH—; R¹ is, independently at each occurrence, selected from thegroup consisting of: halogen, CN, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CH₂F,CHF₂, CF₃, OCH₂F, OCHF₂, OCF₃, CO(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —C(═NH)NH₂; R³ isindependently selected from the group consisting of: H, halogen, CN,CF₃, CO₂H, CO₂(C₁₋₄ alkyl), and C₁₋₄ alkyl; and R⁶ is, independently ateach occurrence, selected from the group consisting of: halogen, C₁₋₄alkyl, CN, OH, CF₃, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H, —CH₂CO₂(C₁₋₄alkyl), NH₂, —CH₂NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl),—CH₂NHCO₂(C₁₋₄ alkyl), —CONH₂, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and


9. The compound of any one of the preceding claims having Formula (I),(II), (IIa), (IIb), (IIc), or (IId), or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a solvate thereof, wherein: L isindependently selected from the group consisting of:—CH₂-phenylene-(CH₂)₀₋₃—, —CH₂O(CH₂)₂₋₄-phenylene-(CH₂)₀₋₁—,—CH₂-phenylene-CONH(CH₂)₀₋₂—, —CH₂-phenylene-CON(C₁₋₄ alkyl)(CH₂)₀₋₂—,—CH₂-pyridinylene-(CH₂)₀₋₃—, —CH₂-pyrimidinylene-(CH₂)₀₋₃—,

wherein each ring moiety is substituted with 0-1 R^(7a); Y isindependently selected from the group consisting of: CH₂, O, NH, N(C₁₋₄alkyl), N(CO₂(C₁₋₄ alkyl)), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; and L₁ is independentlyselected from the group consisting of: a bond and —CH═CH—; R¹ is,independently at each occurrence, selected from the group consisting of:halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN, CH₂F, CHF₂,OCHF₂, NH₂, N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and—C(═NH)NH₂; R³ is independently selected from the group consisting of:H, halogen, C₁₋₄ alkyl, and CN; R⁶ is, independently at each occurrence,selected from the group consisting of: halogen, NH₂, CO₂H, CO₂(C₁₋₄alkyl), CONH₂, CONH(C₁₋₄ alkyl), CON(C₁₋₄ alkyl)₂, —NHCO₂(C₁₋₄ alkyl),—CH₂NHCO₂(C₁₋₄ alkyl), —NHCO₂CH₂CO₂H, —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

and R^(7a) is independently selected from the group consisting of:halogen, C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.
 10. A compound of Formula (III)or Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: L is independently selected from the groupconsisting of:

wherein each ring moiety is substituted with 0-1 R^(7a); Y isindependently selected from the group consisting of: CH₂, O, NH, N(C₁₋₄alkyl), N(CO₂(C₁₋₄ alkyl)), —CONH—, —NHCO—, —CONHCH₂—, —CON(C₁₋₄alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—; L₁ is independently selectedfrom the group consisting of: a bond and —CH═CH—; R¹ is, independentlyat each occurrence, selected from the group consisting of: halogen, C₁₋₄alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN, CH₂F, CHF₂, OCHF₂, NH₂,N(C₁₋₄ alkyl)₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and —C(═NH)NH₂; R^(1b)is independently selected from the group consisting of: H and halogen;R² is independently a 5-membered heterocycle selected from: triazolyland tetrazolyl; R³ is independently selected from the group consistingof: H, halogen, C₁₋₄ alkyl, and CN; R^(6a) is independently selectedfrom the group consisting of: H, halogen, NH₂, CO₂H, CONH₂, CO₂(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CO₂H, —NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.
 11. A compound of Formula (IIIb) orFormula (IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: L is independently selected from the groupconsisting of:

wherein each ring moiety is substituted with 0-1 R^(7a); Y isindependently selected from the group consisting of: CH₂, O, NH, —CONH—,—NHCO—, —CONHCH₂—, —CON(C₁₋₄ alkyl)CH₂—, —OCONH—, —NHCONH—, and —SO₂NH—;L₁ is independently selected from the group consisting of: a bond and—CH═CH—; R¹ is, independently at each occurrence, selected from thegroup consisting of: halogen, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, CO(C₁₋₄alkyl), CN, CH₂F, CHF₂, OCHF₂, —CH₂NH₂, —CH₂NHCO₂(C₁₋₄ alkyl), and—C(═NH)NH₂; R^(1b) is independently selected from the group consistingof: H and halogen; R³ is independently selected from the groupconsisting of: H, halogen, C₁₋₄ alkyl, and CN; R^(6a) is independentlyselected from the group consisting of: H, halogen, NH₂, CO₂H, CONH₂,—NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂CH₂CH(C₁₋₄ alkyl)O(C₁₋₄ alkyl), and

R^(7a) is independently selected from the group consisting of: halogen,C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂.
 12. A compound of Formula (IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: L-Y is independently selected from the groupconsisting of:

wherein each ring moiety is substituted with 0-1 R^(7a); L₁ isindependently selected from the group consisting of: a bond and —CH═CH—;R¹ is, independently at each occurrence, selected from the groupconsisting of: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CO(C₁₋₄ alkyl), CN,CHF₂, and OCHF₂; R^(1b) is independently selected from the groupconsisting of: H and halogen; R² is independently a 5-memberedheterocycle selected from: pyrazolyl, imidazolyl, triazolyl, andtetrazolyl; R³ is independently selected from the group consisting of: Hand halogen; R^(6a) is independently selected from the group consistingof: H, halogen, NH(C₁₋₄ alkyl), and NHCO₂(C₁₋₄ alkyl); and R^(7a) isindependently selected from the group consisting of: halogen, C₁₋₄alkyl, N(C₁₋₄ alkyl)₂.
 13. The compound of claim 12 or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a solvate thereof,wherein: L-Y is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R^(7a); R² isindependently triazolyl or tetrazolyl; and R^(6a) is independentlyselected from the group consisting of: H, halogen, and NHCO₂(C₁₋₄alkyl).
 14. The compound of claim 12 or 13 or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a solvate thereof,wherein: L-Y is independently selected from the group consisting of:

R¹ is independently selected from the group consisting of: F, Cl, Me,OMe, COMe, CN, CHF₂, and OCHF₂; R^(1b) is independently selected fromthe group consisting of: H and F; R² is tetrazolyl; R³ is independentlyselected from the group consisting of: H and Cl; and R^(6a) isindependently selected from the group consisting of: H, F, and NHCO₂Me.15. A compound of claim 1, 2, or 3 having Formula (V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, asolvate thereof, wherein: ring B is independently selected from thegroup consisting of: imidazole and pyridine; and R1 is independentlyselected from the group consisting of: C₁₋₄ alkyl and CH₂NH₂.